Natural products: An evolving role in future drug discovery

European Journal of Medicinal Chemistry 46 (2011) 4769e4807

Contents lists available at ScienceDirect

European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech

Mini-review

Natural products: An evolving role in future drug discovery Bhuwan B. Mishra, Vinod K. Tiwari* Department of Chemistry, Centre of Advanced Study, Banaras Hindu University, Varanasi 221005, India

a r t i c l e i n f o

a b s t r a c t

Article history: Received 7 June 2011 Received in revised form 29 July 2011 Accepted 30 July 2011 Available online 16 August 2011

The therapeutic areas of infectious diseases and oncology have benefited from abundant scaffold diversity in natural products, able to interact with many specific targets within the cell and indeed for many years have been source or inspiration for the majority of FDA approved drugs. The present review describes natural products (NPs), semi-synthetic NPs and NP-derived compounds that have undergone clinical evaluation or registration from 2005 to 2010 by disease area i.e. infectious (bacterial, fungal, parasitic and viral), immunological, cardiovascular, neurological, inflammatory and related diseases and oncology. Ó 2011 Elsevier Masson SAS. All rights reserved.

This manuscript is dedicated to Prof. Goverdhan Mehta, Indian Institute of Science, Bangalore. Keywords: Natural products Clinical development Drug discovery Approved drugs

1. Introduction Natural products have been the major sources of chemical diversity for starting materials while driving pharmaceutical discovery over the past century. Historically pharmaceutical companies have utilized plant extracts to produce relatively crude therapeutic formulations, but with the advancement of antibiotics in the mid-twentieth century, drug formulations of fairly purified compounds have become more typical [1]. The interesting chemicals identified as NPs are derived from the phenomenon of biodiversity in which the interactions among organisms and their environment formulate the diverse complex chemical entities within the organisms that enhance their survival and competitiveness [2]. The therapeutic areas of infectious diseases and oncology have benefited from these numerous drug classes, able to interact with many specific targets within the cell, and indeed for many years have been central in the drug discovery and development. Today, NPs are finding increasing use as probes to interrogate biological systems as part of chemical genomics and related researches. The review summarizes the 3 groups of compounds classified as NPs, semi-synthetic NPs and NP-derived compounds that have undergone clinical evaluation or registration form 2005 to June 2010 by disease area i.e. infectious (bacterial, fungal, parasitic and viral), immunological, cardiovascular, neurological, inflammatory and related diseases and oncology. The compounds which have biological * Corresponding author. Fax: þ91 542 2368174. E-mail addresses: [email protected], [email protected] (V.K. Tiwari). 0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2011.07.057

activities and are derived from natural sources, e.g., plants, animals and microorganisms, have been grouped as NPs. The compounds that are derived from a NP template using semi-synthesis have been grouped in semi-synthetic NPs while the compounds that were synthetically derived or in some cases inspired from a NP template have been classified as NP-derived compounds [3e5]. Previous reviews in this general area come from the 2005 reviews by Kingston and Newman [6,7], Koehn and Carter [8], Paterson and Anderson [9]; the 2006 reviews by Jones et al. [10], Gullo et al. [11], Wilson and Danishefsky [12]; the 2007 reviews by Lam [13], Baker et al. [14], Harvey [15]; the 2008 review by Butler [16]. This review represents a thorough evaluation of publicly available data on NP-derived drugs and templates. Compounds derived from primary metabolites (e.g. steroids, nucleosides, prostaglandins, sialic acid and tyrosine), vitamins (e.g. vitamin D and retinoids), hormones and protein fragments, herbal mixtures, polyamines and porphyrin derivatives have not been listed exhaustively in this review. 2. Drug approval processes An Investigational New Drug (IND) application is submitted to the FDA or EMA before commencement of clinical trials. Once clinical trials are successfully completed, the applicant files a New Drug Application (NDA) in the US or a Marketing Authorization Application (MAA) in Europe to seek approval for marketing the drug. The agency then responds in the form of an ‘approval letter’, a ‘non-approval letter’ or an ‘approvable letter’. An “approval letter”

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allows the applicant to begin marketing the product, while a “nonapproval letter” rejects the application. An ‘approvable letter’ informs the applicants that the agency have completed their scientific review and determined that the application can be approved pending resolution of minor deficiencies identified in the letter or during an inspection of the manufacturing facilities. 3. Natural products based drugs approved during 2005e2010 A total of 19 NP based drugs were approved for marketing worldwide in between the year 2005 to 2010 (Scheme 1), among which 7 are classified as NPs, 10 as semi-synthetic NPs, and 2 as NPderived drugs (Table 1). VeregenÔ (PolyphenonÒ E ointment), a defined mixture of catechins obtained from green tea, is the first ever herbal medicine to receive FDA approval in 2006. VeregenÔ was developed by MediGene AG and launched in the US by Bradley Pharmaceuticals in December 2007 for topical use against genital warts. MediGene signed an agreement with Solvay in 2009 for the licensing and supply of VeregenÔ in Germany, Austria, and Switzerland. In March 2010, Solvay launched VeregenÒ (10% ointment) in Germany [17]. SativexÒ (GW Pharmaceuticals) is the world’s first pharmaceutical prescription medicine derived from the cannabis plant [18]. SativexÒ, a mixture of dronabinol 1 and cannabidol 2, was launched in Canada in April 2005 for neuropathic pain relief in multiple sclerosis [19], and it was also approved by Health Canada in August 2007 as an adjunctive analgesic for severe pain in advanced cancer patients,

reducing the need for the opioid medications. Otsuka Pharmaceutical in February 2007 signed an agreement with GW for further development and marketing of SativexÒ in the USA. SativexÒ efficiently reduces pain in patients with advance cancer [20] and has been recommended by the FDA for direct entry into Phase III trials. In November 2009, GW Pharmaceuticals disclosed that recruitment for a Phase II/III cancer pain trial of SativexÒ had been completed. In March 2010, GW Pharmaceuticals provided an update on the progress of regulatory submission for SativexÒ oromucosal spray for the treatment of the symptoms of spasticity due to multiple sclerosis [21]. Fumagillin (FlisintÒ, Sanofi-Aventis, 3), an antimicrobial lead capable of inhibiting the proliferation of endothelial cells, was isolated from Aspergillus fumigatus [22]. In September 2005, France approved 3 against intestinal microsporidiosis, a disease caused by the sporeforming unicellular parasite Enterocytozoon bieneusi, causing chronic diarrhea in immunocompromised patients [23]. There are presently nine b-lactams (two cephalosporins, six carbapenems and one penem) in clinical trials or undergoing drug registration. Among carbapenem-type b-lactams, doripenem 4 and thienamycin 5 are the ultra-broad spectrum injectable antibiotics. Doripenem (FinibaxÒ, DoribaxÔ) 4, exhibiting a broad antibacterial spectrum [24a] was launched in Japan by Shionogi & Co. in 2005. In October 2007, Johnson & Johnson (J&J) obtained formal FDA approval for use of 4 in intra-abdominal and urinary tract infections [24b]. Tigecycline (TygacilÒ, 6) is among a new generation of antibiotics called glycylcyclines, and is structurally similar to tetracycline 7. It contains a centralized four-ring carbocyclic skeleton substituted at

Scheme 1. Drugs approved during 2005e2010.

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Table 1 NP-derived drugs launched since 2005; lead compounds, classification and therapeutic area [17e117]. Year

Generic name (trade name)

Lead compound

Classification

Disease area

2005 2005 2005 2005 2005 2005 2006 2006 2007 2007 2007 2007 2007 2008 2009 2009 2009 2009 2010

Dronabinol 1/Cannabidol 2 (SativexÒ) Fumagillin 3 (FlisintÒ) Doripenem 4 (FinibaxÒ/DoribaxÔ) Tigecycline 6 (TygacilÒ) Ziconotide 8 (PrialtÒ) Zotarolimus 9 (EndeavorÔ stent) Anidulafungin 11 (EraxisÔ/EcaltaÔ) Exenatide 13 (ByettaÒ) Lisdexamfetamine 14 (VyvanseÔ) Retapamulin 16 (AltabaxÔ/AltargoÔ) Temsirolimus 18 (ToriselÔ) Trabectedin 19 (YondelisÔ) Ixabepilone 20 (IxempraÔ) Methylnaltrexone 22 (RelistorÒ) Everolimus 24 (AfinitorÒ) Telavancin 25 (VibativÔ) Romidepsin 27 (IstodaxÒ) Capsaicin 28 (QutenzaÒ) Monobactam aztreonam 29 (CaystonÔ)

Dronabinol 1/cannabidol 2 Fumagillin 3 Thienamycin 5 Tetracycline 7 Ziconotide 8 Sirolimus 10 Echinocandin B 12 Exenatide-4 13 Amphetamine 15 Pleuromutilin 17 Sirolimus 10 Trabectedin 19 Epothilone B 21 Naltrexone 23 Sirolimus 10 Vancomycin 26 Romidepsin 27 Capsaicin 28 Aztreonam 29

NPs NPs NP-derived Semi-synthetic NP Semi-synthetic Semi-synthetic NP NP-derived Semi-synthetic Semi-synthetic NP Semi-synthetic Semi-synthetic Semi-synthetic Semi-synthetic NP NP Semi-synthetic

Pain Antiparasitic Antibacterial Antibacterial Pain Cardiovascular surgery Antifungal Diabetes ADHD Antibacterial Oncology Oncology Oncology Pain Oncology Antibacterial Oncology Pain Antibacterial

the D-9 position conferring broad spectrum activity. Tigecycline effectively binds to the 30S subunit of bacterial ribosome and blocks the entry of amino-acyl tRNA molecules into the A site of the ribosome, thus inhibits protein translation [25]. Tigecycline was developed by Wyeth [26a] and in June 2005 the FDA approved it for treatment of complicated skin and skin structure infections (cSSSIs) and intra-abdominal infections. Tigecycline was approved in Europe in May 2006, and a supplemental NDA for communityacquired pneumonia (CAP) was submitted to the FDA in October 2007 [26b]. Ziconotide (PrialtÒ, 8) is a synthetic form of the peptide u-conotoxin, which was isolated from the toxin of Conus magus, is an N-type voltage sensitive calcium channel blocker and is proposed to regulate neurotransmission by inhibiting pro-nociceptive neurochemical releases in the brain and spinal cord, thus causing pain relief [27]. In December 2004, the FDA approved 8 when given as an infusion using an intrathecal pump into the cerebrospinal fluid. In 2005, Elan launched Ziconotide 8 in the US and Europe for the treatment of patients suffering from chronic pain. Rights for marketing Ziconotide (PrialtÒ) in Europe was obtained by Eisai in March 2006 [28]. Zotarolimus 9, a derivative of sirolimus 10, is the active principle of the EndeavorÔ stent that inhibits cell proliferation, preventing scar tissue formation and minimizeing restenosis in angioplasty patients [29]. Sirolimus 10 (RapamuneÒ, Wyeth) was originally discovered from the bacterium Steptomyces hygroscopicus as a promiscing antifungal agent [30] and is being used along with other coronary stents against restenosis of coronary arteries due to balloon angioplasty. In July 2005, Medtronic received European approval for the sale of the EndeavorÔ drug-eluting coronary stent that consists of a cobalt-based alloy integrated with a biomimetic phosphorylcholine polymer [31]. In February 2008, Medtronic received FDA approval for the EndeavorÒ in the treatment of coronary artery disease [32a] while CypherÒ (sirolimus-eluting coronary stent) is being marketed by Cordis (Johnson & Johnson) [32b]. Anidulafungin 11 (EraxisÔ in the US, EcaltaÔ in Europe), is a semisynthetic derivative of the fungal metabolite echinocandin B 12. Anidulafungin was originally developed for use against invasive and oesophageal candidiasis and candidemia by Eli Lilly and was licensed to Vicuron Pharmaceuticals, which was purchased by Pfizer in June 2005. Pfizer gained the FDA approval in February 2006 (EraxisÔ in the US) and EMEA approval in July 2007 [33]. Exenatide 13 (ByettaÒ), is a 39 amino acid peptide, structurally similar to glucagon-like peptide-1 (GLP-1) and was isolated from

NP NP NP

NP NP NP NP NP NP

NP

the oral secretions of the poisonous lizard Heloderma suspectum (Gila monster) [34,35]. Among the incretin (human hormone) mimetics, 13 can mimic the antidiabetic or glucose-lowering properties of incretins. Eli Lilly obtained the FDA approval in April 2005 while Amylin Pharmaceuticals gained the EMEA approval in November 2006 for the use of 13 as an adjunctive therapy in type 2 diabetes mellitus [36]. Amylin Pharmaceuticals, Eli Lilly and Alkermes in May 2009 submitted a NDA for subcutaneous dosing of 13 once weekly to the FDA, which was approved in July 2009. Attention-Deficit Hyperactivity Disorder (ADHD), a neurodevelopmental disorder in which dopaminergic and noradrenergic neurotransmission are supposed to be dysregulated, is primarily characterized by the co-existence of attentional problems and hyperactivity. Methylphenidate and amphetamines have been used for ADHD management for many years but due to abuse potentials these drugs are controlled substances [37]. Lisdexamfetamine (VyvanseÔ, NRP104) 14 consisting of dextroamphetamine coupled with the essential amino acid L-lysine was designed by New River Pharmaceuticals to help ADHD. Intravenous administration 14 produces effects similar to placebo and therefore is completely ineffective, however on oral administration it gets converted to D-amphetamine 15 in the gastrointestinal (GI) tract [38]. In February 2007, New River Pharmaceuticals and Shire Pharmaceuticals obtained the FDA approval for use of 14 to help ADHD, and in April 2007 Shire bought New River Pharmaceuticals. Pleuromutilin 16 is a metabolite of fungal origin that binds to the peptidyltransferase and exhibits antibacterial activity by inhibiting protein synthesis in bacteria [39]. Retapamulin (SB-275833) 17, a semi-synthetic derivative of 16, is the first among pleuromutilin antibiotics developed by GlaxoSmithKline for topical use in impetigo caused by Gram-positive Staphylococcus aureus or Streptococcus pyogenes [40]. GlaxoSmithKline gained FDA approval for 17 in April 2007 [68] and the EMEA approval in June 2007 for a 1% retapamulin ointment (called AltabaxÔ in the US and AltargoÔ in Europe). Temsirolimus (ToriselÒ, CCI-779, 18) is a sirolimus 10 derivative and is an intravenous drug developed by Wyeth [41]. It was approved by the FDA in late May 2007 and by the EMEA in November 2007 for use against renal cell carcinoma (RCC) [42]. Temsirolimus 18 is a semisynthetic derivative of sirolimus 10 and is the first mTOR inhibitor developed by Wyeth Pharmaceuticals [43]. Trabectedin (YondelisÒ, ecteinascidin-743, ET-743, 19), a tetrahydroisoquinoline alkaloid produced by Ecteinascidia turbinate [44] is sold by Zeltia and Johnson & Johnson for use in the treatment of

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CH3

CH3

OH

OH

H2C

H3C

O

H3C O

CH3 HO

CH3

CH3

1

2

CH3

H

CH3

HO CH3

O

H

H

CH3

H3C

S

N

OCH3

H N

O

O

O

HO O

CO2H

N H

4

S

NH2 O

O

3 HO

H

CH3

H

H3C

S

N O O

5 HO

H3C

CH3

H3C N

H

OH

CH3

H3C H

H

N

H N

CH3

CH3

N H OH

O

HO OH

CH3 OH

CONH2 O

6 OH

CONH2

OH O

N

O H3C

HO

OH

H3C

NH2

H2N-CKGKGAKCSRLMYDCCTGSCRSGKC-CONH2

O

7

advanced soft tissue sarcoma [45]. Trabectedin binds to the minor groove of DNA and inhibits cell proliferation by disrupting the cell cycle. It was approved by the EMEA in September 2007 for use against soft tissue sarcomas and ovarian cancer. In November 2009, it received its second marketing authorization from the European Commission for the treatment of relapsed platinum-sensitive ovarian cancer in combination with DOXILÒ/CaelyxÒ. Presently, trabectedin is in Phase II trials against pediatric sarcomas, breast and prostate cancers [46]. Ixabepilone (IxempraÔ, BMS-247550, 20) is a semi-synthetic derivative of epothilone B 21 produced by Sorangium cellulosum [47]. Bristol-Myers Squibb (BMS) developed 20 as an anticancer drug that binds directly to b-tubulin subunits on microtubules, leading to the suppression of microtubule dynamics, blocking of cells in the mitotic phase, ultimately leading to cell death. In October 2007, the FDA approved ixabepilone 20 (IxempraÔ) as monotherapy and in combination with capecitabine (XelodaÒ) against metastatic or locally advanced breast cancer patients resistant or refractory to anthracyclines, taxanes, and capecitabine [48].

8

Methylnaltrexone (MOA-728, RelistorÒ by Wyeth, 22), an Nmethyl derivative of naltrexone 23, contains a charged tetravalent nitrogen atom and is unable to cross the bloodebrain barrier, and so has antagonist effects throughout the body [49]. Methylnaltrexone blocks peripheral opioid receptors activated by opioids administered for pain relief and thus useful in management of alcohol and opioid dependence [50]. In May 2007, Wyeth and Progenics filed a NDA for subcutaneous doses of 22 for the treatment of opioid induced constipation and other pain indications. In March 2008, Wyeth and Progenics reported that 22 failed in two Phase III trials for intravenous use in treatment of post-operative ileus. In April 2008, Progenics and Wyeth announced that Health Canada and the FDA have approved 22 for the treatment of opioid induced constipation [51]. As of May 2009 an oral formulation of 22 is under Phase II trials against opioid induced constipation in chronic pain. After acquisition of Wyeth by Pfizer in October 2009, the collaboration is continued by Progenics and Pfizer. Everolimus (LuveniqÔ or LX211, 24), a mTOR inhibiting derivative of 10, is marketed as an immunosuppressant by Novartis under the trade AfinitorÒ for use in advanced renal carcinoma. In

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March 2009 the FDA has approved 24 against advanced renal cell carcinoma after failure of SutentÒ (sunitinib) or NexavarÒ (sorafenib) [52]. Telavancin (VibativÔ, TD-6424, 25), a semi-synthetic analog of vancomycin 26, inhibits bacterial growth through binding to the DAla-D-Ala terminus of the bacterial peptidoglycan precursors [53]. Telavancin was discovered by Theravance, and is being developed in partnership with Astellas [54]. Theravance submitted a NDA in December 2006 and an MAA in May 2007 for use of 25 against Gram-positive cSSSIs, and MRSA, and this was approved in September 2009 by the FDA. Theravance has also submitted 25 to the FDA for a second indication for the treatment of nosocomial pneumonia or hospital aquired pneumonia (HAP). In November 2009, the FDA released a complete response letter to Theravance for telavancin NDA against nosocomial pneumonia. Romidepsin (depsipeptide, FK228, FR901228, IstodaxÒ, 27), a naturally occurring histone deacetylase inhibitor obtained from the bacteria Chromobacterium violaceum [55], was developed and evaluated by Gloucester Pharmaceuticals in various Phase I/II trials sponsored by the National Cancer Institute (NCI) for use against cutaneous and peripheral T-cell lymphoma (TCL) [56]. In November 2009, IstodaxÒ 27 was approved by the FDA against selective

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cutaneous in TCL patients that have received a minimum of one prior systemic therapy [57], while three Phase II trials for multiple myeloma and peripheral TCL are still recruiting patients. In January 2010, Celgene completed the acquisition of Gloucester Pharmaceuticals. Capsaicin 28, an active component of chili peppers belonging to the genus Capsicum, was first isolated in pure and crystalline form by John Clough Thresh in 1876 [58a]. Capsaicin 28 produces a burning sensation when it comes in contact with tissues though binding to the ion channel receptor vanilloid receptor subtype 1 (VR 1) [58b,c]. In November 2009, NeurogesX gained FDA approval for QutenzaÒ (a transdermal 8% patch of 28) against neuropathic pain combined with post-therapeutic neuralgia. In April 2010, NeurogesX launched QutenzaÒ in US and is planning to market it in Europe by Astellas Pharma Europe Ltd. [59]. Aztreonam lysine (CaystonÔ, 29), an inhaled lysine salt formulation [60], wherein the b-lactam ring is alone and not fused to another ring, has been evaluated by Gilead in various Phase III trials against cystic fibrosis (CF) patients having a pulmonary infection of the Gram-negative bacteria Pseudomonas aeruginosa [61]. In February 2010, CaystonÔ was approved by FDA for use in CF patients, however its safety and efficacy is yet to be established in

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13 HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS NH2 H N

NH2

NH2

CH3

CH3

O 15

14

O

CH2 CH3 OH

CH3

O

OH

CH3

O R

OH

O

H

CH3

O H3C H3C

CH3

16 R = OH

OH

O CH3

O

17 R =

S

NCH3

HO O

N

CH3

H

H3C S

N

O N

CH3

H3CO

NH

HO

O O

19

pediatric patients or Burkholderia cepacia colonized patients [62]. The drug is a proprietary formulation of aztreonam, an antibiotic first launched in 1984 for intravenous use. 4. Infectious diseases 4.1. Antimicrobials 4.1.1. Antibacterial agents NP-derived drugs have been crucial for anti-infective drug discovery, and the many of antibacterial drugs currently in clinical use are NPs or were designed using NP templates. Several antibiotics have been discovered simply by measuring zones of inhibition of bacterial strains on agar plates by applying whole broth or extracts obtained from microbial ferments. Mining of the bacterial genome is providing new avenues for recognition of crucial targets for the discovery of antibacterial agents with reduced side effects [63]. Despite having complex structures the development of a NP to an antibacterial drug mainly depends on its ability to penetrate bacterial cell membranes [64]. The success of penicillin

CH3

CH3

CH3

CH3 H3C CH3 H3C

N X

HO

CH3

O

S H3C

O

CH3

18 OH O

O

CH3

O

H3C

O O

CH3

O

OCH3

O H3C

O

O

20 X = NH 21 X = O

OH

CH3 O

OH

O

led to unparalleled efforts by government, academia and the pharmaceutical industry to discover other compounds from natural sources for the treatment of bacterial infections, resulting in nearly all novel classes of antibiotics being from NP sourced scaffolds through 1962. Since the commercialization of penicillins in the 1940s, b-lactams that inhibit the formation of peptidoglycan cross links in the bacterial cell wall leading to bacterial death, have been the mainstay for treating community-acquired infections [65]. Ceftobiprole medocaril (BAL-5788, 30) is a cephalosporin antibiotic with excellent activity against P. aeruginosa, MRSA and penicillin-resistant Streptococcus pneumoniae [66]. Ceftobiprole 30 is given intravenously [67] and was filed for regulatory approval in the US and Europe in July 2007, after the successful completion of pivotal Phase III registration trials by Basilea Pharmaceutica and J&J affiliated Cilag GmbH International for the treatment of cSSSIs. In November 2008, the FDA declined to approve 30 and recommended completion of two new and well-controlled studies for safety and efficacy accessment against cSSSIs. In addition, various Phase III trials are underway for HAP/CAP. Ceftaroline acetate (PPI0903, TAK-599, 31), originally discovered by Takeda is known to

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4775

HO O

H3C

CH3

O

O HO

22

O

N

HO

H

N

Br

O

HN

O

HO O

HO

NH

O

O

O

H3C

OH OH

N H

H2N S

R1 = R2 =

N H

O NH

PO3H2

HO

H3C

O H N

CH3

CH 3

O

N

O S

O O

OH

O

OH H3CO

CH3

O 27

29 CH3

NH

S

O

CH3 CO2H

N

R2 H N

S

O

NH2

O

N COOH

H N

O

O

NH

O

CH3 H3C

O

HO

CH3

HN NH

Cl HN

HO

O

O

O

CH3

CH3

HO

H N

Cl

O

CH3

24 OH

O

O

O

H3C

CH3

O

CH3

O

O

23

N H

CH3

O

HO

HO

CH3

O

O

25

OH

N

H

O

R1

O

HO

CH3

N H 28

CH3

26 R1 = H, R2 = H

exhibit efficient antibacterial activity against penicillin-resistant S. pneumoniae. Cerexa licensed 31 from Takeda and the drug is currently in Phase II clinical trials by Forest Laboratories to use against cSSSIs and CAP [68]. Tebipenem pivoxil (ME-1211, L-084, 32) is an advanced carbapenem being evaluated as a broad-spectrum antibiotic under Phase III trials in Japan by Meiji Seika for otolaryngological/respiratory infections [69]. Tomopenem (CS-023, RO4908463, R1558, Daiichi Sankyo, 33) for use against common nosocomial infections [70], and PZ601 (SM-216601, Protez, licensed from Dainippon Sumitomo, 34) for use against MRSA and Pseudomonas aeruginosaare, both are in Phase II trials [71]. ME1036 (CP5609) 35, a DHP-1-stable parenteral carbapenem in which a 7-acylated imidazo[5,1-b]thiazole-2-yl group is substituted at carbapenem moiety, was licensed by Cerexa and Forest Laboratories from Meiji Seika Kaisha. ME1036 has excellent in vitro activity against multidrug-resistant (MDR) Staphylococci and Enterococcus faecalis. ME1036 exhibits a broad Gram-negative activity of the carbapenems (activity against ESBLproducing Escherichia coli and Klebsiella pneumoniae), except for P. aeruginosa and is under Phase I evaluation [72]. Pfizer is evaluating sulopenem (CP-70429) 36, and a prodrug, PF-3709270, in Phase I trial [73].

Faropenem daloxate (SUN-208, BAY-56-6824) 37 is a penemtype b-lactam licensed to Replidyne by Daiichi Suntory Pharma to market it in conjunction with Forest Pharmaceuticals [74]. In December 2005, Replidyne submitted a NDA to the FDA for use of 37 against acute bacterial sinusitis (ABS), acute exacerbation of chronic bronchitis (AECB), CAP and uncomplicated skin and skin structure infections (uSSSIs). In March 2007, the FDA agreed for Phase III development of 37 with placebo-controlled trials, one each in ABS and AECB along with two non-inferiority CAP trials. These additional trials have delayed the launch of drug. Dalbavancin (ZevenÒ, BI-397, 38) is a second-generation lipoglycopeptide antibiotic and semi-synthetic derivative of the teicoplanin analog A40926 39. It was discovered by Biosearch Italia and is being developed by Pfizer to use against cSSSIs [75]. Vicuron Pharamaceutical (now part of Pfizer) in February 2005 filed a NDA to use 38 for the treatment of cSSSIs. In December 2007, the FDA released an approval letter to Pfizer for use of 38 against cSSSIs adult patients, including MRSA [76]. However, based on feedback from regulatory authorities, Pfizer has withdrawn the marketing applications for running another Phase III trial for 38. Oritavancin (NuvocidÔ, LY-333328, 40), a chloroeremomycin 41 derivative obtained through semi-synthesis was discovered and

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N

OH H N

N H2N

S

N

O

O

H

S

O

HO

OH HO

P

N

H N

O

O

N

S

H3C N

H H

N

CH3

N

35

H N

32

HH

O

developed by Eli Lilly and acquired by InterMune in 2001 and transferred to Targanta Therapeutics in 2005. Oritavancin has the ability to attach with two types of peptidoglycans and exerts antibacterial activity through inhibition of cell wall synthesis. Targanta submitted a NDA for approval of 40 to the FDA in February 2008 [77], which was accepted for standard review with an established action date in December 2008. In December 2008, the FDA stated that there was insufficient data to approve 40. Additionally, Targanta submitted a MAA for 40 to the EMEA that was accepted for review in June 2008. The vancomycin-cephalosporin heterodimer TD-1792 42, combining the antibacterial activities of a glycopeptide and a b-lactam in one molecule, has been designed to target 2 key bacterial cell wall synthesis targets. TD-1792 42 is in clinical development by Theravance, who has successfully conducted Phase II trials for safety and efficacy accessments against cSSSIs, including MRSA. In July 2007, Theravance disclosed that 42 met primary and secondary endpoints in a non-inferiority trial compared to vancomycin 26 [78]. Ramoplanin factor A2 (ramoplanin, 43), is the major component of the lipopeptide antibiotic drugs derived from strain ATCC 33076 of Actinoplanes [79] which exerts antibacterial activity by inhibiting bacterial cell wall synthesis. Ramoplanin factor A2 43 can form Ushaped structures with the ability to bind and capture Lipid II (C35MurNAc-peptide-GlcNAc), a specific intermediate in membrane formation [80]. Oscient Pharmaceuticals licensed the North American rights for orally active ramoplanin 43 from Vicuron and evaluated it in Phase II trials for GI tract infections caused by Clostridium difficile [81,82]. The NXL-103 (XRP2868), discovered by Sanofi-Aventis, is an orally available mixture (70:30) of two semi-synthetic streptogramins, flopristin (RPR132552A, streptogramin A-type, 44) and

N

O 36

HO

S

N

O

H3C

NH2

CH3

H H

O

NH2

O

HO OH

S

CH3 S

O

S

NH

34 HH

S

H

N

O

O

O

CH3

O

CH3

N

H3C

O

S

N

H3C

OH

N

O

N

O

O

NH

O O

S O

N H

S

N

OH

O

N

33

CH3

N HO

H3C H3C CH3

O

N

O

H3C O

HO

CH3

H

O

O S

S

H

H3C

N

S

H OH

OH

CH3

H H

O

S

N

O

31 OH

O CH3

N

H

O

O

O H N

O

O

30

O

CH3 N

N

N

N

CH3

O O 37

linopristin (RPR202698, streptogramin B-type, 45) [83]. Streptogramins inhibit bacterial protein synthesis through the synergistic binding of streptogramin A & B components to different sites on the peptidyltransferase domain of the 50S ribosomal subunit [84]. In October 2008 Novexel announced for positive Phase II trials of NXL103 against CAP and cSSSIs, including MRSA [85]. MerLion Pharmaceuticals in July 2007 initiated Phase I trials of friulimicin B 46, a lipopeptide antibiotic having activity against Gram-positive bacteria through complex formation with bactoprenol-phosphate, leading to the inhibition of peptidoglycan, and teichoic acid biosynthesis [86]. Friulimicin B is produced by Actinoplanes friuliensis HAG 010964 and its structure was confirmed after the crystal structure of amphomycin tsushimycin (A-1437B, 47), an aspartic acid analog of 46 published in late 2005 [87]. Moli1901 (duramycin, 2262U90, 48), a polycyclic peptide produced by Streptomyces cinnamoneum [88], is under clinical development by AOP Orphan in collaboration with Lantibio in Europe. Moli1901 enhances chloride transport and increases fluid secretion in vitro, thus has clinical indication against CF [89]. After successful Phase I trials [90], aerosolized 48 was evaluated under Phase II clinical development in Europe with positive results announced in adolescents and adults with CF in March 2007. Lantibio is also investigating an ophthalmic solution of 48 in Phase II clinical trials for the treatment of dry eye syndrome. Omiganan 49, an analog of antibacterial peptide indolicidin 50 which was originally purified from neutrophils of bovines [91], has significant activity against infections caused by antibiotic-resistant and sensitive bacteria. Indolicidin consists of 13 amino acids and has the highest tryptophan content among the known proteins with amidation at the carboxyl terminus [92]. Like other cationic peptides, omiganan exerts antibacterial activity through interaction with the bacterial cytoplasmic membrane, and was developed by MIGENIX

B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807

and licensed to Cadence Pharmaceuticals for catheter-related infections (coded OmigardÔ, CPI-226, MBI-226), and Cutanea Life Sciences for dermatological diseases (coded as CLS001, MX-594AN). A Primary end point was not achieved in a Phase III trial by Cadence Pharmaceuticals, and additional Phase III trials using a gel-based formulation are underway. Cutanea Life Sciences have successfully evaluated 49 in Phase II trials (2007) while the Phase III trials for treatment of rosacea, a chronic inflammatory skin disorder, are underway. Among the group of macrolide antibiotics, erythromycin 51, obtained from actinomycetes, has ability to bind with the peptidyltransferase site of 50S ribosomal subunit, and can exert antibacterial activity by the inhibition of protein synthesis [93]. Cethromycin (ABT-773, RestanzaÔ, 52), EP-420 53 (by Enanta Pharmaceuticals), and BAL-19403 54 (by Basilea), are three semisynthetic ketolide derivatives of 51 that are in clinical development. Cethromycin was developed originally by Abbott Laboratories [94], and later acquired by Advanced Life Sciences to use against CAP [95], and post-exposure to anthrax inhalation. A NDA by Advanced Life Sciences for the use of 52 against mild-to-moderate CAP was

4777

accepted by FDA in December 2008 [96]. In placebo-controlled non-human primate studies by Advance Life Sciences, RestanzaÔ has demonstrated a clinically and statistically significant survival rate in anthrax, plague and tularemia. In September 2009, orphan drug designation was granted to 52 by the FDA for use in plague and tularemia. A bridged bicyclic derivative, EP-420 (EP-013420, 53) is under Phase II clinical trials by both Enanta and Shionogi for treatment of CAP [97]. BAL19403 is a macrolide antibiotic whose antibacterial spectrum covers clinical isolates of Propionibacterium acnes with mutations in the 2057 to 2059 region of 23S rRNA conferring resistance to erythromycin and clindamycin [98]. Basilea has reported the first clinical data for 54 in the treatment of acne [99]. The first approved ketolide, telithromycin (KetekÒ, 55) was evaluated in Phase II/III clinical trials by French pharmaceutical company Hoechst Marion Roussel (later Sanofi-Aventis) in 1998. Latter on, telithromycin was approved by the European Commission in July 2001 and subsequently went on sale in October 2001. In the US, 55 had received the FDA approval in April 2004 against the respiratory infections. Telithromycin displays bactericidal activity

4778

B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807

OH H3C

NH2 O CH3 O

OH

O

O O HN

N H

O OH

Cl

O

H N O

N H

O H N O

O

O

NH2 NH

N

H N

N H2N S

Cl

O

N H

H N

CH3 CH3

CH3

OH OH

HO

O

OH

Cl

O HO

OH

O

O

42 H

S

N

N CO2H

by blocking the progression of the growing polypeptide chain through binding with the 50S subunit of ribosome [100]. Tiacumicin B (OPT-80, PAR-101, 56), an actinomycete-derived macrolactone, isolated by Abbott [101a], is in Phase III trials against C. difficile-associated diarrhea (CDAD) by Optimer Pharmaceuticals [101b]. Tiacumicin B exerts antibacterial activity by inhibition of RNA synthesis in bacteria [101c]. The PTK-0796 (MK2764, 57), an aminomethylcycline with excellent activity against both Gram-positive and Gram-negative strains, was discovered and evaluated by Paratek in various Phase II trials against common hospital infections. The PTK-0796 is a bacterial protein synthesis inhibitor that was in-licensed by Novartis form Paratek for collaborative Phase III clinical development. In October 2009, Novartis gained exclusive rights for marketing 57 as oral broad-spectrum antibiotic against MRSA, MDR S. pneumoniae and vancomycinresistant enterococci [102]. Eisai has designed the second-generation lipid A antagonist eritoran (E5564, 58) [103a] from Rs-DPLA 59, a non-toxic lipid A analog originally isolated from Rhodopseudomonas sphaeroides [103b]. Eritoran inhibits the endotoxin response through antagonism of the Toll-like receptor 4 (TLR4) [104a], and is currently in Phase III development by Eisai against sepsis caused by Gramnegative bacteria [104b]. CBR-2092 60, a hybrid antibiotic combining rifamycin SV and 4H-4-oxo-quinolizine, is being developed by Cumbre Pharmaceuticals. The studies with S. aureus have shown that CBR-2092 brings rifampin-like effects to RNA synthesis and quinolone-like effects to DNA synthesis in rifampin-susceptible and resistant strains, respectively [105]. CBR-2092 is supposed to exert antimicrobial activity through combined effects on RNA polymerase, DNA topoisomerase IV, and DNA gyrase. Currently, CBR-2092 is in Phase IIa

trial by Cumbre for the treatment of infections caused by grampositive cocci [106]. 4.1.2. Antifungal agents Fungal infections of the bloodstream and organs, e.g., peritonitis, meningitis and pneumonia, are among the important causes of morbidity and mortality in organ transplant recipients [107]. Despite major advances in drug chemotherapy, fungal infections are still a challenge, particularly in the growing number of immunosuppressed patients seen in modern medical facilities. Despite having a cell wall, fungi are more similar to mammalian cells than to bacteria at the cellular level; therefore treatment of mycotic infections is very difficult [108]. Fewer antifungal candidates are undergoing clinical evaluation in which only 2 are NP-derived (aminocandin, 61 and SPK-843, 62). Echinocandins that inhibit the synthesis of glucan in cell wall are known to exert limited toxicity in human due to lack of biological target, 1,3-b-D-glucan synthesis, and thus, are significant against invasive infections by Candida species [109]. Among semi-synthetic echinocandins, caspofungin (first launch 2001, CancidasÒ, Merck), micafungin (first launch 2002, MycamineÒ/FunguardÒ, Astellas) and and anidulafungin 11 (first launch 2006, EraxisÔ/EcaltaÔ, Pfizer) have been approved since 2001. Deoxymulundocandin 63, originally isolated from the fungus Aspergillus sydowii [110], is the lead compound of aminocandin (NXL-201, IP960, HMR-3270, 61), an investigational drug with excellent activity against Candida albicans and C. tropicalis [111]. In December 2006, Novexel and Indevus signed an agreement over the out-licensing of 61. The Dutch company APARTS BV has successfully completed Phase I trials for SPK-843 62, obtained through semi-synthesis of patrician-A 64 produced by Streptomyces

B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807

aureofaciens. SPK-843 can destabilize the cell membrane of fungi like other polyenes [112]. Kaken Pharmaceuticals has restarted Phase II trials of 62 for treatment of systemic mycosis. APARTS BV has acquired world wide rights for the development of 62 and a license for Japan has been signed while contracts are still pending with US and European companies [113]. 4.1.3. Antiparasitic agents Despite the fact that several NPs have been tested against protozoans followed by the implementation of heroic vectorcontrol measures, the incidence of parasitic infections has increased globally [114]. The use of medicinal plants against parasitic diseases has been traced from ancient records i.e. Cinchona calisaya (bark), Strychnos pseudoquina (bark), Deianira erubescens (roots and leaves) and Remijia ferruginea (bark) [115].

4779

In the 1970s, artemisinin 65, an important antimalarial drug was identified from traditional Chinese medicine Artemisia annua. Arterolane (RBx11160, OZ-277, 66), a synthetic trioxolane modeled on artemisinin 65 pharmacophore, is being evaluated in combination with piperaquine (a synthetic bisquinoline antimalarial drug) to fight against malaria by Ranbaxy [116]. In May 2009, Ranbaxy announced for commencement of Phase III clinical trials of 66 in combination with piperaquine phosphate in India, Bangladesh and Thailand to treat Plasmodium falciparum malaria [117]. Paromomycin 67 (HumatinÔ, King Pharmaceuticals), an aminoglycoside antibiotic first isolated from Streptomyces krestomuceticus [118a], was developed as therapeutic agent against visceral leishmaniasis by the Institute for OneWorld Health [118b]. Paromomycin has orphan drug status and was approved by the DrugController General of India in September 2006 against visceral

4780

B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807

NH H-Ala-Lys-Gln-Ala-Ala-Ala-Phe-Gly-Pro-Phe-Abu-Phe-Val-Ala-HOAsp-Gly-Asn-Abu-LysOH S

S

S 48

ILRWPWWPWRRK-NH2 O

49

H3C

H3C

O

OH OH

H3C N

CH3 HO O

H3C O O

O

O

O

CH3

O

O

N

HO

O

H3C H3C

O

S

CH3

CH3 HO O

H3C O O

H3C

O CH3 OCH3 H

O

O

O

CH3 CH3

CH3 H3C O

H3C O

CH3 HO O

leishmaniasis (VL) [119]. Paromomycin 67 is an off-patent antibiotic marketed in the US to treat intestinal parasites. In February 2008, King Pharmaceuticals discontinued the sale of HumatinÔ but the substance is continually available in the US from another manufacturer. 4.1.4. Antiviral agents The single celled viruses represent the smallest existing lifeform causing most common (i.e. cold, influenza, chickenpox and cold sores) to greatest human health risk (i.e. ebola, AIDS, avian influenza and SARS). Significant research and development over the last 25 years into antiviral drug discovery has resulted in the identification of important antiviral drugs like betulinic acid 68, a triterpenoid obtained from bark of Betula pubescens [120a]. Betulinic acid was originally identified as a weak inhibitor of HIV replication by Lee and co-workers at the University of North Carolina [120b]. Betulinic acid can inhibit topoisomerase I [121a], and is being evaluated in Phase I trials as a cancer chemo-preventive agent. Bevirimat (PA-457, 69), extracted from a Chinese herb Syzygium claviflorum is under Phase IIb trial in combination therapy by Panacos [121b]. Bevirimat is believed to inhibit HIV through maturation inhibition and blocks HIV maturation by inhibiting the final step of the HIV Gag protein processing. In December 2007, Panacos announced the results of Phase IIb trial while in January

H3C

N CH3

O

CH3

OCH3

O CH3 O

CH3 53

CH3

52

O H3C N

O

O

CH3

O

CH3

N

N

N

N

CH3 HO O

CH3

N O

H3C

O CH3 H3C O

H3C

N

H3C

CH3

CH3

51 N

H3C H N

CH3 OH

CH3

N

CH3

OCH3

O

N

50

CH3

H3C HO

ILPWKWPWWPWRR-NH2

CH3 OH CH3

54

2009, Myriad Genetics announced for the acquisition of all rights from Panacos for 69 [122]. Ribavarin 70 is a NP-derived compound having structure based upon the Streptomyces-derived nucleoside antibiotics pyrazomycin and showdomycin, isolated in the 1960s, was marketed as ‘Rebetol’ in the US by Schering Plough with Valeant Pharmaceuticals until 2005. Taribavirin (ViramidineÒ, ribamidine, 71), a liver-targeting prodrug of ribavirin 70 [123], is under Phase II/III development by Valeant Pharmaceuticals against chronic hepatitis C virus (HCV) in treatment-naive patients. Taribavirin is the standard treatment with interferon a-2b for HCV, and gets converted inside the liver by adenosine deaminase to 70. In 2006, Valeant had announced the results of Phase III trials, in which 71 failed to meet the noninferiority efficacy endpoints. In 2007, Valeant initiated a Phase IIb trial for 71 at higher doses, and reported the final results in June 2009 against HCV [123]. MBI-3253 (celgosivir, 6-O-butanoylcastanospermine, 72), a semisynthetic analog of castanospermine 73, was first isolated from the seeds of Castanospermum australe [124a]. Castanospermine is an inhibitor of some glucosidase enzymes, and has excellent antiviral activity [258]. In January 2009, MIGENIX disclosed the completion of Phase II clinical studies [124b] of 72 as a ‘triple combination’ (with peginterferon a-2b and ribavirin 70) and a ‘double combination’ (with peginterferon a-2b) in HCV patients. An exclusive option agreement

B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807

HO O

H3C H3C

H3C

H3C OH O O

OCH3 H3C

H3C O

N

O OH

Cl OH Cl

H3C

CH3 OCH3 CH3 HO O

O

O

H3C

H3C

N CH3

H3C

CH3

O

CH3

N

CH3

OH

CH3 OH CONH2

OH OH O

O 57 OH

O

O

HO

HN

O

H2O3PO

O

O

HN OPO3H2 O O

H3CO

CH3

O

O

O

HO

HN

O

O

O

HO O

CH3

O

O HN OPO3H2 O O

CH3 H3C

H3C

58

CH3

O

O

HO

CH3

H3C

H

N

H N

OCH3 O

H3C H

55

CH3

H2O3PO

OH

O H3C H3C

O

H CH3 H3C O

H3C

OH O

O

56

N O

O

H3C

N N

OH

CH3

H

CH3

H3C O

4781

CH3

59

H3C

CH3 CH3 CH3

O H3CO

OH CH3 OH

OH O OH

H3C

CH3 NH

O O CH3

O N

O

F

N

OH

N 60

with United Therapeutics Corporation (UTC) was signed by MIGENIX for further development of 72 which was discontinued in April 2009. MIGENIX are currently seeking other strategic options for their drug development programe [125]. Cyclosporin 74, a fungal cyclic peptide consisting of 11 amino acids obtained from Beauveria nivea, is an immunosuppressant that exerts antiviral activity through inhibition of cyclophilin. However, development of 74 as antiviral drug is not possible due to calcineurinrelated and immunosuppressive side effects [126]. NIM 811 (SDZ

N

CO2H

N

CH3

CH3

NIM 811, cyclosporin 29, MeIle4-cyclosporin, 75), a NP discovered by Sandoz (now Novartis) with comparatively less immunosuppressive activity (1700 times less than cyclosporin 74) with favorable safty profile [127], is in Phase I trials for anti-HIV and HCV activity. Debio025 (UNIL025, MeAla3EtVal4-cyclosporin, 76) is a cyclophilin inhibitor that displays 7000 times less immunosuppressive activity than 74, and is in various Phase IIb trials by Debiopharm for the treatment of HCV [128]. Debio-025 acts with a novel mechanism of action by binding to cyclophilin A (CypA) [129a]. In February 2010, Novartis in-

4782

B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807

licensed the exclusive rights to develop and market 76, as potential first-in-class antiviral agent except in Japan [129b]. 4-Methylumbelliferone 77, an active ingredient of nutraceutical product HeparvitÒ by MTmedical Institute of Health and BioMonde, is currently in Phase II development against HBV and HCV [130a]. The chinese academy of military medical sciences have started the clinical evaluation of HIV-1 integrase inhibitor [130b], 1,5-DCQA (1,5-di-O-caffeoylquinic acid, 78), extracted from Inula Britannic, for the treatment of HIV. In 2006, Chinese scientists have initiated the human trials of 78 to treat HIV/AIDS and hepatitis B [131]. WAP-8294A2 (JA-002, 79), a major component of the antibacterial complex produced by Gram-negative Lysobacter species, is potentially effective against the treatment of MRSA, cSSSIs, pneumonia and septicemia [132]. WAP-8294A2 exerts antibacterial activity by selective interaction to membrane phospholipids,

causing sever damage to membrane while remains inactive against Gram-negative bacteria, yeasts and fungi. The aRigen Pharmaceuticals are developing injectible, gel, and cream of 79 in various Phase I/II trials against MRSA and acne. In August 2009, New Energy and Industrial Technology Development Organization (NEDO) in Japan had selected the aRigen Pharmaceuticals for funding twothirds of the R&D costs for the development of 79 as first-line anti-MRSA product candidate under the Innovation Promotion Program (IPP) until February 2011 [133]. 4.2. Halted or discontinued compounds in infectious diseases Rifalazil (ABI-1648, KRM-1648, 80) is a new generation semisynthetic rifamycin B 81 derivative, that was evaluated by ActivBiotics, and failed in a Phase III trial for the treatment of the

B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807

intermittent claudication, associated with peripheral arterial disease [134]. In December 2007, ActivBiotics went on sale for all the proprietary assets that opened a new hope for 80 to re-enter clinical evaluation with a different company. Incyclinide (Col-3, 82), is a chemically modified tetracycline which was evaluated by NCI and CollaGenex for the treatment of various cancers (including a Phase II trial against Kaposi’s sarcoma), and rosacea. In July 2007, CollaGenex discontinued their acne programme with 82 due to disappointing results in Phase II trial [135].

4783

The two orally bio-available pleuromutilin derivatives, 565154 and 742510, being evaluated in Phase I trial, were dropped by GSK in September 2007 pipeline products. Artemisone (BAY 44-9585) 83, a semi-synthetic derivative of artemisinin 63 having low lipophilicity and negligible neuro- and cytotoxicity in vitro and in vivo, was first synthesized at Hong Kong University [136]. BAY 44-9585 83 exhibits efficient activity against malarial parasite compared to current artemisinin. Bayer was evaluating 83 as a potential antimalarial [137] in various Phase II trials but in last few years, there is no information available about the further development of 83.

4784

B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807

Calanolide A 84, a coumarin inhibiting non-nucleoside reverse transcriptase [138] was first obtained from Calophyllum lanigerum trees in Malaysia with potent activity against HIV-1 [139], was licensed and evaluated to Phase II clinical trials by Sarawak Medichem Pharmaceuticals. After purchase of the remaining 50% of Sarawak Medichem and full rights from Advanced Life Sciences by Sarawak Government in late 2006, no subsequent announcement for further drug development has been made.

treatment of neuropathic pain in cancer patients [143b]. Shanghai Institute of Material Medica has synthesized Debio 9902 (ZT-1, 90) [144], a prodrug of 87, and licensed it to Debiopharm. In June 2007, Debiopharm announced the positive results of a Phase IIa trial for safty and efficacy of 90 in treatment of mild Alzheimer’s disease. An Independent Data Safety Monitoring Board (IDSMB) in March 2008, recommended Debiopharm to continue Phase II study of 90 without modification in Alzheimer’s patients. In October 2008, Debiopharm announced for starting of tablet formulation bridging study under IND for Alzheimer’s patients [145]. Lobeline 91, a piperidine alkaloid found in Lobelia species (such as Lobelia inflata, Lobelia tupa, Lobelia cardinalis, Lobelia siphilitica) and Hippobroma longiflora, has been used traditionally as an emetic, respiratory stimulant and more recently as a tobacco smoking cessation agent [146]. Lobeline acts as a VMAT2 ligand [147a,b] that reduces the methamphetamine induced dopamine release. Yaupon Therapeutics and NIH are evaluating 91 in Phase II trials as a dopamine modulating agent for the treatment of methamphetamine addiction and ADHD [147c]. Anabaseine 92, a neurotoxic principle identified from marine worms of the phylum Rhynchocoela [148a], stimulates a wide variety of nicotinic acetylcholine receptors (AChRs), especially the neuromuscular [e.g. a12b1gd (embryogenic) or a12b1g3 (adult)] and a7 AChRs [148b]. The 3-(2,4-Dimethoxybenzylidene)-anabaseine (DMXBA also called GTS-21, 93), a synthetic derivative of 92, was evaluated by Kem’s University of Florida in a sponsored research by Taiho Pharmaceutical against Alzheimer’s disease [149]. In April 2006, CoMentis (previously Athenagen) disclosed for acquiring the assets of Osprey Pharmaceuticals, who had licensed GTS-21 93 from the University of Florida. CoMentis have completed a Phase II trial in Alzheimer’s disease and are assessing 93 in various Phase I and II trials for assessment of safety and cognitive improvement in ADHD patients. Tetrodotoxin (TectinÔ, Wex Pharmaceuticals) 94, a potent neurotoxin extracted and purified from the puffer fish [150a] by

5. Neurological diseases Neurological diseases involve the disease of central, peripheral, and autonomic nervous systems. Historically, the plant alkaloids such as morphine 85 (from Papaver somniferum), cocaine (from Erythroxylon coca) and physostigmine 86 (from Physostigma venenosum) have been used to treat sever pain and central nervous system (CNS) diseases. A sesquiterpene alkaloid, huperzine-A 87, an acetylcholinesterase (AChE) inhibitor [140a] isolated from firmoss Huperzia serrata [140b], is under clinical development by Chinese scientists for treatment Alzheimer’s disease. NIA, a division NIH is evaluating 87 when administered orally in Phase II trials against Alzheimer’s disease [141]. Morphine-6-glucuronide (M6G) 88, a glucuronide derivative produced by metabolism of 85 in human body, was evaluated as analgesic by CeNeS Pharmaceuticals under Phase II and III trials in Europe [142a]. In 2007, a successful Phase III study demonstrated that 88 effectively reduces pain equivalent to 85 with significant reduction in vomiting, post-operative nausea, sedation and other common side effects. In June 2008, a biopharmaceutical company PAION acquired the CeNeS Pharmaceuticals and announced for completion of two Phase III trials by November 2008 [142b]. KRN-5500 89, a spicamycin derivative produced by Streptomyces alanosinicus [143a], was evaluated for safety and efficacy in Phase I trial by DARA BioSciences against neuropathic pain. Currently, DARA BioSciences are conducting Phase IIa trials of 89 as an intravenously (IV) administred medicine for the H3C

O

CH3

CH3

H3C

CH3

O

CH3

CH3

CH3

O

H3CO

OH CH3

OH

OH

O

H3CO O

O CH3

N

H

OH

CH3

OH

H3C

CONH2 O

O

N O

O

O

H3C

H

O

CO2H

S

CH3 CH3

O

O O O

O

O

H3C

CH3 82

CH3

81 CH3

H OH

O NH

CH3

CH3 N

80

O

OH

O

HO

H

OH

O

N

O

OH

H3C

O

O

OH CH3

CH3 NH

H3C

OH

O

83

OH CH3

84

O

B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807

means of a proprietary process developed by Wex Pharmaceuticals, is able to block the action potentials in nerves through binding to sodium channels in cell membrane [150b]. Wex in colaboratin with Chinese medical institute, are evaluating 94 for the treatment of cancer pain [151a] and management of opiate withdrawal symptoms in Phase III and I trials, respectively. Wex Pharmaceuticals are also conducting Phase IIa clinical study for 94 against neuropathic pain caused by chemotherapy in patients with cancer [151b]. Conotoxins, a group of neurotoxic peptides obtained from cone snail of genus Conus, are supposed to modulate the activity of ion channels [152]. Xen-2174 95, a 13 amino acid peptide with 2 cysteine bridges that targets the norepinephrine transporter (NET) [153], was originally discovered by researchers at the University of Queensland who characterized the various effects of Conus marmoreus venom. Xenome are evaluating 95 in Phase II trials against acute post-operative pain and chronic pain in cancer patients who are no longer responsive, minimally responsive, or intolerant to morphine and hydromorphone [154]. One of the major capsaicinods, capsaicin 28, has been found significant in clinical conditions like osteoarthritis [155a], post-herpetic neuralgias, psoriasis [155b] and diabetic neuropathy [155c]. As discussed earlier that QutenzaÒ (an 8% trans-dermal patch of capsaicin 28) has been approved in 2009, Anesiva are evaluating different formulations of capsaicin 28 (coded 4975, ALGRX 4975) for treatment of severe post-surgical pain, post-traumatic neuropathic pain and musculoskeletal diseases in various clinical trials. In December 2008, Anesiva announced to attain primary end point while evaluating AdleaÔ (ALGRX 4975) in a Phase III clinical trial against acute pain following orthopedic surgery [156a]. Winston Laboratories undertook Phase III trials of civamide (cis-capsaicin, zucapsaicin, WL-1001) for the treatment of episodic cluster headache and knee osteoarthritis. In October 2008, a NDS by Winston was filed in Canada for CivanexÒ (civamide 0.075%) for releving osteoarthritis pain. In February 2009, an orphan drug designation to CivanexÒ was given by FDA with NON release to Winston Pharmaceuticals in October 2009 [156b]. Phlorizin 96, a polyphenolic glucoside obtained from apple tree, lowers glucose plasma levels and improves insulin resistance by inhibiting sodium glucose co-transporters (SGLTs) [157]. Poor intestinal absorption and inactivation by lactase-phlorizin hydrolase were serious drawbacks that restricted the development of 96 as drug [158]. Dapagliflozin (BMS-512148) 97, an analog of 96 and selective inhibitor of SGLT2 is being evaluated by by Bristol-Myers Squibb in partnership with AstraZeneca as a potential treatment for type 2 diabetes [159]. In October 2009, the BMS announced the results of Phase III trial of 97, a 24-week study showing statistically greater mean reductions of body weight compared to individuals receiving placebo [160]. Among other phlorizin-inspired derivatives in development, the Phase II trials for GSK-189075 in treatment-naive type 2 diabetes mellitus have been completed by GlaxoSmithKline in June 2008. Resveratrol 98, a triphenolic stilbene isolated from a variety of plants has been reported significant in the treatment of cancer, ischemic injuries and cardiovascular disease [161]. In 2003, Howitz and co-workers reported that resveratrol 98 is an agonist of Saccharomyces cerevisiae silent information regulator (Sir2) protein, a class III histone deactylase whose presence results in extended lifespan of S. cerevisiae, Caenorhabditis elegans and Drosophila melanogaster [162]. In 2006, Italian scientists announced the positive result of 98 supplementation in Nothobranchius furzeri, a fish that demonstrated an increased median life span by 56% [163]. Sirtris proprietary formulation of 98, SRT-501, targets SIRT1 and acts by increasing mitochondrial activity, hence is significant against diabetes and obesity. Sirtris have successfully completed

4785

the Phase IIa trial demonstrating oral doses 1.25 or 2.5 g of SRT501 are safe and tolerable when administered twice daily for 28 days in type 2 diabetes. Similar Phase IIa cancer trial with SRT501 is underway [164]. Cannabinoids, a unique group of secondary metabolites found in the cannabis plant (Cannabis sativa) and others, are responsible for the plant’s peculiar pharmacological effects [165]. CP 7075 (IP 751, ajulemic acid, CT-3, 99) is a synthetic cannabinoid that suppress inflammatory cytokines, including IL-1b and matrix metalloproteinases (MMPs) through a peroxisome proliferator-activated receptor (PPAR) g-mediated mechanism [166]. Pre-clinical toxicology and pharmacology studies of 99 was evaluated by Indevus Pharmaceuticals and later in October 2007, the drug was licensed to Cervelo Pharmaceuticals for further manufacturing and pre-clinical studies in preparation for Phase I trials in neuropathic pain [167]. 5.1. Halted or discontinued compounds in neurological diseases CEP-1347 (KT-8138) 100 is a semi-synthetic derivative of K-252a 101 [168a], a CaM kinase and phosphorylase kinase inhibiting alkaloid isolated from Nocardiopisis species [168b,169], was evaluated by Cephalon and H Lundbeck AS against Parkinson’s disease. CEP-1347 100 was discontinued by May 2005 due to lack of efficacy in various Phase II/III trials [169]. Devacade 102 is an orally active cholecystokinin A (CCK A) antagonist whose structure was based upon asperlicin 103 [170], a mycotoxin derived from Aspergillus alliaceus. ML Laboratories, who evaluated 102 in Phase II trials for the enhancement of opioid pain relief, has discontined the clinical development in May 2005. Cognetix were associated with clinical developments of conotoxins isolated from marine cone snail. Contulakin G (CGX-1160) 104 is an orphan drug designated lead of Cognetix that has completed a Phase Ib clinical trial against chronic and intractable pain. The further clinical evaluations of CGX 1160 104 and conantokin-G (CGX1007) 105 are on hold until more funding can be obtained. ACV1 (Vcl.1, 106), a neuronal nicotinic receptor antagonist that displays selectivity for the a9a10 subtype, was identified by screening some uncharacterized conopeptide sequences from the venom duct of C. victoriae using PCR [171a]. ACV1106 was evaluated by Metabolic Pharmaceuticals against neuropathic pain in diabetes and post-herpetic neuralgia. In August 2007, Metabolic announced for discontinuation of Phase IIa trials of 106 due to less activity against the human a9a10 nAChR receptor compared to equivalent rat receptors [171b]. Torrey-Pines Therapeutics (formally Axonyx) evaluated phenserine 107, an AChE inhibitor showing disease modifying action by reducing plaque through inhibition of APP synthesis as well as provides symptomatic relief [172]. In November 2008, QR Pharma licensed 107 from TorreyPines, and evaluated PosiphenÒ (a (þ)enantiomer of 107) against Alzheimer’s disease. In May 2009, QR Pharma reported the failour of 107 in placebo-controlled Phase III trials. In April 2009, QR Pharma received investment from Ben Franklin Technology Partners for further clinical development of 107. In February 2010, QR Pharma gained US Patent for the use of PosiphenÒ against cognitive impairments combined with Down syndrome [173]. Gantacurium chloride (AV430A, GW280430A, 108), an ultrashort-acting, non-depolarizing surgical neuromuscular blocker (NMB), was evaluated by GSK in Phase I trials demonstrating excellent safety and potent neuromuscular blocking effects [174]. Avera in 2002 gained acquisition assets from GSK and completed Phase I and II developments of 108. Currently, Avera are seeking to out-license the development and commercialization rights for 108. Some phlorizin-inspired derivatives discontinued from development are KGT-1681 (GSK and Kissei), TS-033 (Taisho) and YM-

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HO

H3C

O H

H

H3C

CH3

N

RO

N H

CH3

N H

H3C

H2N

OH

H N

O HO

O

N N H

N NH N

OH

OCH3

OH N

O

N

HO

O

H

H3C

O

87

O

89

CH3

CH3

86

OH H3C

N

O

HO HO

N

H3C

O O

HO2C

85 R = H; 88 R=

H N

H

OCH3

CH3 91

HO N H3CO

Cl 90

H2N

N HN H HO

HO

O O OH

OH

O

O

OH

O

HO OH

O 96

OH

Cl

OH 97

NGVCCGYKLCHOC

OH

94

93

HO

OH

HO O

N

92

HO HO

HO

N

N

OH

O

CH3

CO2H

95

OH HO

H3C OH 98

543 (Astellas). GlaxoSmithKline by 2009 have discontinued development of remogliflozin etabonate (KGT-1681, 109), a SGLT-2 inhibitor licensed from Kissei Pharmaceutical. Taisho Pharmaceutical in October 2008 announced for discontinuation of TS-033, an investigational compound for treatment of diabetes [175a]. As on May 2009, Astellas have discontinued the development of YM-543 for the treatment of type 2 diabetes [175b]. 6. Cardiovascular and metabolic diseases NPs have made a major impact in the treatment of cardiovascular and metabolic diseases. Simvastatin (ZocorÒ, Merck & Co), a hypolipidemic drug belonging to the class of statins, is a synthetic derivate of Aspergillus terreus fermentation product and is known to exert the lipid-lowering activity through inhibition of 5-hydroxy-3methylglutarylcoenzyme A (HMG-CoA) reductase. Orlistat, a potent natural inhibitor of pancreatic lipases, is the saturated derivative of

H3C

CH3 99

H3C CH3

lipstatin, isolated from bacterium Streptomyces toxytricini, and is used to treat the obesity [176]. The antihypertensive angiotensinconverting enzyme (ACE) inhibitors (e.g. captopril, ramipril and quinapril) are derived from the snake venom peptide teprotide. Ilepatril (AVE-7688, 110), is an endopeptidase inhibitor (NEP) currently in Phase IIb/III trials by sanofi-aventis against hypertension while in Phase II development for diabetic nephropathy [177]. Migalastat (AmigalÔ, AT1001, 1-deoxygalactonojirimycin, 1-deoxygalactostatin, 111) was first reported by semi-synthesis from galactonojirimycin (galactostatin) 112 isolated from Streptomyces species. Migalastat is a pharmacological chaperone that enables the restoration of correct folding by stabilizing the protein structures through binding with them. In May 2006, orphan designation was granted by the European Commission to Amicus Therapeutics for use of 111 against Fabry disease, which was transferred to Shire Pharmaceutical in June 2008. As of January 2010, AmigalÔ is in Phase III trials as monotherapy by Amicus

B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807

Therapeutics in conjunction with Shire Pharmaceuticals for the treatment of Fabry disease [178]. Isofagomine (PliceraÔ, AT2101, 113), a synthetic aza-sugar designed to mimic the carbocation transition state used by glycosidases [179], was evaluated by Amicus Pharmaceuticals in Phase II trials against Gaucher’s disease, a lysosomal storage disorder caused by b-glucocerebrosidase deficiency [180a]. In October 2009, Amicus disclosed the positive results of Phase II randomized and open-label clinical trial for two dose regimens (225 mg three days on/four days off and seven days on/seven days off) [180b]. Ruboxistaurin (LY333531, 114), a protein kinase C (PKC) inhibitor, was evaluated by Eli Lilly against microvascular complications in diabetes mellitus [181]. In February, 2006, Lilly submitted a NDA for 114 in diabetic peripheral retinopathy. In August 2006, Lilly received an “approvable” letter from the FDA with a request of another Phase III trial for additional efficacy data but no new clinical trials are running. SCH 530348 (TRA, 115), an oral thrombin receptor (PAR-1) antagonist [182a] based on himbacine 116, isolated from the plant Galbulimima baccata, is under clinical development by ScheringPlough to prevent atherothrombotic events in patients with ACS, MI, stroke, or disease of peripheral arteries [182b,c]. SCH 530348 is in Phase III clinical development against cardiovascular diseases such as atherosclerosis, ischemia, myocardial infarction and stroke. Trodusquemine (MSI-1436, 117), a sulfated aminosterol isolated from Squalus acanthias (dogfish shark) along with squalamine 118 and other steroids [183a], is in clinical development by Genaera Corporation for the treatment of type 2 Diabetes. MSI-1436 is a potent appetite suppressant (protein tyrosine phosphatase 1B inhibitor) [183b,c] that causes weight loss without metabolic rebound, and normalize fasting blood glucose, blood cholesterol, and triglyceride levels in obese animals. Genaera is currently evaluating 117 as an IND in a second Phase I trial against obesity using an ascending single dose in overweight type 2 diabetes. Ouabain (g-strophanthin, 119), is among some cardiac glycosides found in the ripe seeds of Strophanthus gratus, and the bark of Acokanthera ouabaio. Ouabain can inhibit the Naþ/Kþ-ATPase of plasma membrane especially at the higher concentrations attainable in vitro or with intravenous dosage [184]. Digoxin 120 is

4787

a purified cardiac glycoside isolated from the foxglove plant Digitalis lanata [185a] and also occurs in the human adrenal gland and has been considered significant in heart conditions, namely atrial fibrillation, and atrial flutter. Rostafuroxin (PST 2238, 121), an ouabain antagonist syntesized by Sigma-Tau, is in Phase II trials for the treatment of chronic arterial hypertension [185bed]. Mitemcinal (GM-611, 30 -N-dimethyl-11-deoxy-30 -N-isopropyl12-O-methyl-11-oxo-8,9-didehydroerythromycin, 122) is an orally administered motilin agonist discovered by Chugai Pharma. Mitemcinal lacks the antibiotic properties of erythromycin and increases the amplitude & frequency of antral contractions, and initiates gastric contractions. Chugai has completed Phase I trials of 122 in Japan while Phase II trials in US are ongoing for the treatment of diabetic reflux oesophagitis, and idiopathic gastroparesis [186]. Mitemcinal is also under Phase II trials by Chugai for treatment of the irritable bowel syndrome (IBS). Pyridoxamine (PyridorinÔ, 123) is a vitamin B6 analog based on a pyridine ring bearing hydroxyl, methyl, aminomethyl, and hydroxymethyl substituents [187a]. BioStratum have evaluated 123 in two Phase II trials, and observed significant retardation in the progression of diabetic nephropathy. In KK-A(y)/Ta mice model, 123 improves the urinary albumin/creatinine ratio though inhibition of advanced glycation end products (AGEs) and antioxidant effects in the kidneys. In October 2006, BioStratum licensed the programme to NephroGenex. Currently, NephroGenex has initiated a new Phase IIb clinical trial (PYR-210) for safety and efficacy assessments of 123 in slowing the progression of nephropathy in patients with type 2 diabetes [187b]. Taisho Pharmaceutical is evaluating 123 (coded as K-163) in Phase II trials against diabetic nephropathy. In January 2009, the FDA ruled for regulation of 123 as a pharmaceutical drug, and awarded it with a fast track drug designation. 6.1. Halted or discontinued compounds in cardiovascular and metabolic diseases 1-Deoxynojirimycin (AT2220, moranoline, 124) is obtained by catalytic hydrogenation or borohydride reduction of antibiotic nojirimycin 125 (isolated from Streptomyces species) [188]. Later,

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H N O

O

NH

H3C

CO2H

O

HO

H N

R

HO

OH

O

H N

H

H

113 O

O H

O

H

H3C

N

N 118 R = H H

H3C

NH2

CH3

OSO3H

N H

N H O

O

H

H

H

H N

CH3

H OH

H

OH

O

O

H

OH

OH

H OH HO 119

OH

H

121

CH3

OH H3C

O

HO

H3C O

H3C O H3C

H3C H3C O

NH2 HO

O

OH

OH

H3C

H

H H

OH

CH3

OH N

OH

O

OH

H 120

CH3

CH3 HO O

H3C O

H3C O

CH3 N

CH3 CH3

OCH3

O CH3 O

CH3

H

H O

O O

CH3 O 123

CH3

H3C

CH3 HO HO HO

N

116 CH3

117 R =

O O

H

115 F

H3C

H

H3C

CH3

HO

H

H3C

114

R

H

O

N

CH3

O

CH3

O

H3C

N

N

OH

HO

OH

OH 111 R = H 112 R = OH

SAc 110 H N O

H3C

H N

CH3 122 OH CH3

H

O

B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807

Yagi and co-workers isolated 124, which they called moranoline, a NP occurring in the root bark of various Morus species and microorganisms [189]. Amicus launched the Phase II trials for 124 in June 2008 against Pompe disease [190a,b]. In February 2009, Amicus put the development on hold by suspending enrollment for the Phase II trials [190c]. In September 2009, Amicus Therapeutics announced that they are planning to initiate a Phase I trial for pharmacokinetic studies of 124 in muscle tissues of healthy adults. The FDA has agreed for proposed Phase I study by Amicus and kept 124 on a partial hold [190d]. MC-1 (pyridoxal 5-phosphate, 126), a naturally occurring vitamin B6 metabolite and P2X receptor antagonist, was successfully evaluated in Phase II trials as monotherapy as well as in combination with angiotensin blocker lisinopril (coded MC-4232) by Medicure for the treatment of chronic cardiovascular, and metabolic diseases [191]. In March 2008, Medicure couldn’t met the end point in a Phase III trial of 126 to acertain the effects on cardiovascular death combined with nonfatal myocardial infarction. Currently, Phase II trials of 126 for the treatment of chronic cardiovascular disease, and Phase III trials for Coronary Artery Bypass Graft Surgery (CABG) by Medicure are on clinical hold. Medicure is now planning for a Phase II trial of 126 in lipid lowering during metabolic syndrome, a group of symptoms that promote coronary artery disease, stroke, and type 2 diabetes [192]. 7. Immunological, inflammatory and related diseases Autoimmune diseases are the results of overactive immune response of the body against substances and tissues. This may be localized to certain organs or particular tissue affecting the basement membrane of lung and kidney. Aspirin, a NPs derived compound discovered in the late 1890s is still being used as an analgesic and anti-inflammatory drug. Salbutamol is a short-acting b2-adrenergic receptor agonist marketed by GlaxoSmithKlinen for relief of asthma and chronic obstructive pulmonary disease. The launch of NPs, e.g., cyclosporin 74 (1983), tacrolimus (1993), sirolimus 10 (1999) and mycophenolate sodium (2003), and the semi-synthetic NPs mycophenolate mofetil (1995) are surving as significant immunosuppressive drugs. Everolimus (LuveniqÔ or LX211, 127), an mTOR inhibitor and derivative of 10 is marketed as immunosuppressant by Novartis under the trade names CerticanÒ in organ transplantation. Voclosporin (ISA-247, R1524) 128, a calcineurin inhibitor [193a] and semi-synthetic derivative of cyclosporine-A 74, is in a Phase IIb trial to prevent the rejection of kidney graft while in Phase III development against psoriasis. Isotechnika has licensed 128 to Lux Biosciences for ophthalmic indications. In March 2009, the three Phase III trials for 128 (coded LX211) oral capsules against uveitis were completed successfully by Lux Biosciences. In February 2010, Lux Biosciences filed a NDA with the FDA and a MAA with the EMA for 128, under LuveniqÔ to use in the treatment of non-infectious uveitis involving the posterior eye segment, which were accepted by respective agencies in March 2010 [193b]. TAFA-93, a prodrug of

H N

HO

HO HO

O

OH OH 124 R = H 125 R = OH

O

CHO

R

H3C

N 126

P

OH OH

4789

the mTOR inhibitor sirolimus 10 was developed and successfully evaluated by Isotechnika in Phase I trials against transplant rejection [193c]. Eupatilin 129 is a pharmacologically active flavone derived from Artemisia argyi, a Korean traditional medicine significant for chronic diarrhea [194a]. Dong-A Pharmaceutical are evaluating DA-6034 130, a synthesized analog of eupatilin 129, in various Phase I and Phase II trials to use in the treatment of dry eye and gastritis, respectively [194b]. The synthetic isoflavone derivative NV-52, a thromboxane synthase (TXS) inhibitor is being developed as a treatment for inflammatory bowel diseases by Novogen. Novogen have completed Phase IIa and IIb trials and found that once-daily dosaging of NV-52 has demonstrated no detectable side effects. Novogen also have NV-07a in Phase II trials for antiaging as well as for protection of human skin from sunlightinduced damage [194c]. 7.1. Halted or discontinued compounds in immunological and inflammatory diseases Fingolimod (FTY720, 131) is an immunosuppressant agent derived from fungal metabolite myriocin 132 isolated from fungus Isaria sinclairii [195]. Fingolimod 131 produces immunosuppressant activity after phosphorylation in vivo by sphingosine kinase to yield an active metabolite that is a potent agonist of sphingosine-1phosphate (S1 P) receptors 1, 3, 4 and 5 [196]. Novartis and Mitsubishi Tanabe were evaluating 131 for the treatment of multiple sclerosis in US & European Phase III and Japanese Phase II trials. In a Phase III clinical trial in kidney transplantation, the drug 131 was found to be no better than the existing standard of care. Both Novartis and Mitsubishi Tanabe have discontinued clinical development of 131 for transplantation. Ancrod (ViprinexÔ), a defibrinogenating agent which binds with high specificity to fibrinogn [197a], was extracted from Malayan pit viper venom. In January 2005, fast-track status was given to ViprinexÔ by the FDA for treatment of acute ischemic stroke, a condition that arises due to blockage of blood vessels supplying brain. Neurobiological Technologies have evaluated ViprinexÔ in various Phase III trials, which failed to show benefits in patients suffering from acute ischemic stroke [197b]. In January 2009, Neurobiological Technologies have suspended the ViprinexÔ development program and have decided not to develop it further for the treatment of acute ischemic stroke [197c]. 8. Oncological diseases 8.1. Small-molecule anticancer agents 8.1.1. Plant-derived compounds Camptothecin 133, a quinoline based cytotoxic alkaloid isolated from the bark and stem of Camptotheca acuminata [198], shows significant anticancer activity through inhibition of topoisomerase I. BioNumerik are developing KarenitecinÒ (BNP-1350, 134) as an investigational anti-tumor agent among camptothecin class of chemotherapy drugs [199]. In February 2008, BioNumerik Pharmaceuticals have initiated the Phase III clinical trial of 134 in advanced ovarian cancer patients [200]. Diflomotecan (BN80915) 135, an analog of 134, is currently under Phase II clinical development by Ipsen against advance metastatic cancers [201]. In November 2003, Novartis gained rights to develop and commercialize (ST-1481, 136) from Sigma-Tau as an oral topoisomerase I inhibitor. Gimatecan is currently in Phase II development to use in treatment of solid tumors [202]. Elomotecan (BN-80927, LBQ707, R-1559, 137), a cytotoxic agent inhibiting topoisomerase I and II, is being evaluated by Ipsen against certain advanced metastatic

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cancers (e.g. colon, breast and prostate) [203]. As of April 2009, 137 is a promising Phase I pipeline by Ipsen in oncology. DRF 1042 138, is an orally active camptothecin derivative that was evaluated by Dr. Reddy’s Laboratories in Phase I trials for the treatment of various cancers [204]. In September 2006, Dr. Reddy’s Laboratories collaborated with ClinTec International for development of 138 in Phase II/III trials. SN2310 139, an injectable prodrug of SN-38 140, is currently in Phase I clinical trial for safety, pharmacokinetics and tolerance accessment in cancer patients. In September 2006, Sonus initiated a Phase I study of 139 which is presently ongoing, and after merger of Sonus Pharmaceuticals with OncoGenex Technologies in May 2008, the new company, OncoGenex Pharmaceuticals have listed 139 in oncology pipeline to address cancer [205].

CH3 HO HO

HO HO2C

NH2

131

OH CH3 NH2 OH

O 132

Combretastatin A-4 phosphate (ZybrestatÔ, CA4P, 140) is a prodrug of combretastatin A-4 141, a most potent among the combretastatin class of natural stilbenoid phenols obtained from Combretum caffrum, South African Bush Willow [206]. Combretastatin A-4 141 acts as a reversible tubulin depolymerizing agent and causes tumor-associated endothelial cells to change from a flat to a round shape, thus plugging the blood vessels, and deprives the tumor from oxygen and nutrients [207]. Oxigene are evaluating 140 as a vascular disrupting agent (VDA) in various Phase I/II/III trials [208]. As on September 2008, 140 is under Phase III trial against anaplastic thyroid cancer (ATC). In November 2009, Oxigene announced for positive results from Phase II trial of 140 in non-small cell lung cancer (NSCLC) [209a]. Ombrabulin (AVE8062) 142, another water soluble derivative of 141 was licensed to SanofiAventis from Ajinomoto, is under Phase III trials in advanced soft tissue sarcoma (STS) patients [209b]. Combretastatin A-1 diphosphate (OXi4503, 143), a pro-drug of combretastatin A-1 144, is metabolized by oxidative enzymes that are present in various solid and liquid tumors and tumor infiltrates resulting in the creation of reactive oxygen species (ROS) and an orthoquinone metabolite which covalently binds to proteins and nucleic acids (DNA), causing direct cytotoxic effects on tumor cells [210]. OXGENE are evaluating 144 in various Phase I trials against advanced-stage solid tumors. Noscapine (CB3304, noscapine, 145), a microtubule targeting antitussive benzylisoquinoline alkaloid isolated from plants of the Papaveraceae family, is currently under

B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807

Phase I/II trials by Cougar Biotechnology against multiple myeloma, a cancer of plasma cells [211]. Vinblastine (Alkaban-AQÒ, VelbanÒ, 146), a vinca alkaloid first isolated from Catharanthus roseus [212], inhibits the assembly of microtubules by binding to tubulin. An intravenous injection of 146 is significant against non-Hodgkin’s lymphoma, Hodgkin’s disease, Kaposi’s sarcoma, TCL, breast, testicular, lung, neck and head cancers and choriocarcinoma [213]. The fluorinated vinca alkaloid, vinflunine (JavlorÒ, 147) [214a] was licensed by Bristol-Myers Squibb from Laboratoires Pierre Fabre that was terminated in November 2007. In June 2008, after positive Phase III trial in the metastatic treatment of bladder cancer, 147 was submitted for registration with the EMEA by Laboratoires Pierre Fabre. In June 2009, Laboratoires Pierre Fabre announced for receiving a positive

4791

opinion with recommendation for marketing authorization of 147 in the metastatic treatment of bladder cancer [214b]. Paclitaxel (TaxolÔ, AbraxaneÔ, 148) [215a], a mitotic inhibitor used to treat patients with lung, ovarian, breast cancer, head and neck cancer, and advanced forms of Kaposi’s sarcoma, was isolated originally from Taxus brevifolia. Paclitaxel 148 stabilizes microtubules and interferes with the normal breakdown of microtubules during cell division [215b]. Bristol-Myers Squibb (BMS) are associated with commercial development of 148. Sanofi-Aventis have designed cabazitaxel (XRP6258) 149 and larotaxel (XRP9881) 150 as poor substrates for membraneassociated P-glycoprotein (P-gp), since overexpression of P-gp is crucial in taxane resistance [216]. Cabazitaxel 149 and larotaxel 150 are currently in a Phase III trials to use in the treatment of patients

R O

N

HO Si(CH3)3

136 R =

N

F

O

H3C

134 R =

CH3

H3C

H3C

H3C

R

O

CH3

HO

N

O OCH3 H3CO

O

NH2

H N

O

H3C HO

OR

OH

OCH3

OCH3

OCH3

142

H3CO

140 R = OPO3Na2

OCH3 OCH3

143 R = PO3Na2 144 R = H

141 R = OH

O O

H3C

N

N

O

145

CH3 H

O

O

N

CH3

O H3C

H

OH H

CH3

CH3

OH N 146

H

CH3

F

F CH3

H

N

N H H3CO2C H3CO

O

OR

OCH3

OCH3

O

O

N

O

OCH3 H3CO

CH3

O

O

O

O

HO

139 H3C

O H3C

CH3 O

O

N 138

N 137

OH

O

Cl

CH3

CH3

O

N O

HO

135

N

H3C

O

O

CH3

N

N

C(CH3)3

O

O

N

N 133 R = H

H3C

F

OAc CO2CH3

N

N H H3CO2C

CH3

OH N

H3CO 147

H

CH3

OAc CO2CH3

4792

B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807

with pancreatic and hormone-refractory prostate cancers [217]. DHA-paclitaxel (TaxoprexinÒ) 151, a fatty acid conjugate of paclitaxel 148, is currently under pivotal Phase III trial by Luitpold Pharmaceuticals against metastatic melanoma [218]. Spectrum is evaluating a third generation intravenously as well as orally available taxane, ortataxel (IDN-5109, BAY-59-8862, 152) [219] having similar toxicity/tolerance profile to paclitaxel 148 in Phase I/II trials. Ortataxel 152 displays activity in tumors resistant to TaxolÒ and as of June 2009, the drug is in Phase II trials in taxane-refractory solid tumors [220]. Milataxel (MAC-321, TL-00139) 153, an orally bioavailable taxane and poor substrate for P-gp is under Phase II clinical development by Wyeth Pharmaceuticals to use in the treatment of colorectal neoplasms [221]. Tesetaxel (DJ-927, 154), an orally bioavailable semi-synthetic taxane that was evlaulated by Genta in various Phase I/II trials in patients with advanced gastric and breast cancer [222]. A Phase II clinical trial of 154 is undergoing in advanced melanoma patients with a normal serum lactate dehydrogenase (LDH) and have progressed after one chemotherapy regimen. Genta are also planning to explore the activity of 154 in advanced castrate-resistant prostate cancer (CRPC). Other taxanes, i.e. TPI-287 155 by Tapestry Pharmaceuticals for the treatment of advanced pancreatic cancer [223], BMS-188797 156 by Bristol-Myers Squibb for treatment of

patients with advanced malignancies are currently in Phase II clinical development [224]. Acronycine 157, an alkaloid isolated in 1948 from the stem bark of a Australian Rutaceous tree, Acronychia baueri, displays activity against a panel of murine solid tumor models, including S-180 and AKR sarcomas, X-5563 myeloma, S-115 carcinoma and S-91 melanoma [225]. A benzoacronycine derivative S23906-1 158 shows antineoplastic activity by inhibition of DNA synthesis and also causes an irreversible S-phase blockage in the cell cycle and efficiently triggeres apoptosis in several cancer cell types. Currently, Laboratories Servier are evaluating 158 in various Phase I trials against solid tumors [226]. Homoharringtonine (omacetaxine mepesuccinate, CeflatoninÒ, 159), a myelosuppressive alkaloid originally isolated from the evergreen tree Cephalotuxus fortuneii, inhibits synthesis of Mcl-1 protein and induces apoptosis [227a]. In October 2004, the European Commission granted orphan designation to Stragen France SAS for 159 against acute myeloid leukemia (AML). In January 2009, sponsorship was transferred to ChemGenex Europe SAS, France. In January 2009, an Orphan Drug designation was given to 159 by the FDA to use in the treatment of myelodysplastic syndromes (MDS). In September 2009, ChemGenex submitted a NDA for 159 under OmaproÔ (omacetaxine mepesuccinate) to the FDA for the

CH3 CH3

O

O

NH

H3C H3C

O

O

O CH3

O

CH3

OH

HO

148

O

CH3 CH3

O

NH

H3C

O

H3C H3C

O

CH3

O O

HO

H3C

150

O

O

O

NH

H3C H3C

O

OR 151

O

O

H3C

O

H3C

CH3

O H3C

OH

CH3

152

O CH3 OH

CH3 O

O

O

O O

O

NH

O

O

O O

H3C

O

O O H3C

O OH H3C O CH3 O CH3

H3C O

H O

H

6 CH3

CH3 CH3 O CH3

O

O O

O

H3C

O CH3 OH

CH3 HO

O

O

O CH3

O

H

R=

NH

O

O

O

CH3 CH3 O CH3

O O O H3C

CH3 HO

H

O

CH3

OH

O CH3 CH3 O

CH3

OH 149

O

O

O

O

H3CO

O

CH3 NH

O

CH3

H O

O

O

O CH3OH

CH3

OH HO 153

O

H O

O

O H3C

O

B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807

treatment of chronic myelogeneous leukemia (CML) patients who have a particular gene mutation (T315I mutation) or failed in imatinib therapy. In March 2010, Oncologic Drugs Advisory Committee of the FDA recommended for validated test to identify the T315I mutation prior to approval of OmaproÔ [227b]. ChemGenex are also evaluating 159 in Phase II clinical trial to use in the treatment of patients with refractory or relapse AML who have failed intensive chemotherapy. 30 -O-methyl-nordihydroguaiaretic acid (NDGA) 160, a lignan originally isolated from the creosote bush Larrea divaricatta is known to exhibit significant antipromoter, anti-inflammatory, and antineoplastic activities. NDGA 160 probably inhibits activation of insulin-like growth factor receptor (IGF-1R) and the c-erbB2/HER2/ neu receptor, causing retardation in tumor cell proliferation [228]. Terameprocol 161, a transcription inhibitor and synthetic derivative of 160, was licensed to Erimos by The Johns Hopkins University to use in oncology. Terameprocol 161 induces apoptosis in cancer cells by inactivation of maturation promoting factor (CDC2/cyclin B complex) and survivin production and phosphorylation [229]. Erimos are evaluating 161 in various Phase I/II trials against solid tumors, glioma and leukemia [230].

CH3 CH3 O CH3 O

NH

H3C

O

N

CH3 CH3

O F

OH

HO

154 O

OCH3

N R

O

H

O

O

NH

OH CH3

O

OR OR OR 160 R = H

HO

HO

155

F

F

O

O

H3C

O

O

H3C

O

OCH3 OCH3

163

O

H N

F

CH3 CH3

F H3C

O

O O

O

OCH3

O

O

F

O O

H

H3CO H3CO

CH3

159

O O

OH

O

O

O

O

O O

O

F

O

O

O

OH

F

O O

O

H

H

O H3CO O

O

OH

O

F

H3C

161 R = CH3

162

CH3 CH3

O CH3 OH

CH3

156

F

O CH3 O

CH3

O

F

H

O

O H3C

H3C H3C

O

CH3

O

H3C H3C

O

O

OH

H3CO

CH2

O

O H3C

O

157 R = H 158 R = OAc H3C

NH

O

CH3 CH3

R

CH3 CH3 O CH3

CH3

O CH3

OH C 3

O

CH3

O

Epipodophyllotoxin (F11782, 162), a naturally occurring nonalkaloid extracted from root of Podophyllum peltatum [231a], is a non-intercalating dual inhibitor of both topoisomerases I and II that impairs the binding of the enzyme to DNA, but does not stabilize the cleavage complex [231b]. Tafluposide 163 is a derivative of 162 and is currently in Phase I clinical development for antitumor activity by Pierre Fabre [232]. Ingenol 164, extracted from the sap of Euphorbia peplus is under clinical development by Peplin Biotech for topical treatment of certain skin cancers, such as basal cell carcinomas and squamous cell carcinomas [233]. In November 2009, Peplin merged with LEO Pharma. Peplin’s oncology lead, ingenol mebutate (PEP005, 165), a PKC activator and derivative of 164, is currently in Phase III clinical development against actinic keratosis (AK). In December 2009, LEO Pharma announced the positive results of 165 in two Phase III trials for the treatment of AK lesions on head, including the face and scalp. In February 2010, LEO Pharma disclosed to meet the primary end point with disappearance of AK lesions in non-head locations during a Phase III study [234]. Daidzein 166, an isoflavone occurring in a number of plants and herbs including Pueraria Mirifica, soybeans and soy products,

CH3

N O

4793

OCH3 OH

P OH O

O

H3C RO HO HO 164 R = H O

HO CH3

165 R =

CH3

4794

B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807

exhibits clinical indication against tumors [235]. Novogen are evaluating a series of synthetic analogs of 166 in various preclinical and clinical trials to use in the treatment of caners. Phenoxodiol 167 [236], a synthetic analog of 166, was licensed by Marshall Edwards from Novogen for development as a chemosensitizing agent in combination therapy with platinum drugs against chemoresistant ovarian cancer and also as a monotherapy to use in the treatment of prostate and cervical cancers. Phenoxodiol 167 is supposed to inhibit selectively S-1-P (sphingosine-1-phosphate), the overexpressed pro-survival regulator and makes cancer cells more sensitive to chemotherapy. Phenoxodiol 167 is under Phase III investigations by Marshall Edwards to restore chemosensitivity in patients with ovarian cancer resisting platinum drugs. A Phase II trial of 167 in patients with castrate and noncastrate prostate cancer is also underway [237]. Triphendiol (NV-196), an orallydelivered chemosensitizing derivative of 167 that was licensed to Marshall Edwards by Novogen, is under Phase I trials for use in combination therapy against cholangiocarcinoma, advanced prostate cancer and melanoma. An orphan drug status was granted to 167 by the FDA for cholangiocarcinoma, prostate cancer and stage IIb-IV malignant melanoma. In January 2009, FDA granted IND approval to 167. Genistein 168, a soy-derived antineoplastic phytoestrogen, inhibits protein-tyrosine kinase and induces cell differentiation, is under Phase I/II trials by Astellas, Bausch & Lomb for treatment of tumors. Genistein 168 is also supposed to inhibit topoisomerase II, resulting in DNA fragmentation and apoptosis. Gossypol 169, a polypenolic aldehyde extracted from cottonseed plant of genus Gossypium, family Malvaceae, acts as an inhibitor for several dehydrogenase enzymes [237]. Ascenta Therapeutics are developing ()-gossypol (AT-101, 169) as an orally-active, pan-Bcl-2 inhibitor that causes apoptosis in cancer cells through working as BH3 mimetic. In June 2009, Ascenta Therapeutics announced the promising results of Phase I/II study of 169 in prostate, brain and lung cancers. In October 2009, Ascenta Therapeutics announced the results of a Phase I trial for two combination regeims containing 73 in patients with malignant brain tumor [238]. ASA 404 (vadimezan, AS1404 and DMXAA, 170), a derivative of flavone-8-acetic acid 171, was discovered originally at Auckland Cancer Society Research Centre. The flavonoid 171 works as a tumor-VDA that was in-licensed by Antisoma in 2001 [239]. In April 2007, Novartis AG signed an agreement with Antisoma for worldwide rights and co-selling of 170 in the US. As on April 2008, after a positive Phase II trial, 170 is currently in Phase III clinical development by Novartis as a second line treatment for NSCLC. A second Phase III trial for 170 as a first line treatment for NSCLC has been discontinued in March 2010 [240]. b-Lapachone (ARQ501, 172), a naphthoquinone derived from Tabebuia avellanedae, exerts anti-tumor effect by a rapid and sustained increase of the pro-apoptotic protein E2F-1, as well as induces expression of cyclin dependent kinase inhibitor 1A (CDKN1A or p21) [241a]. ArQule are currently evaluating 172 as a combination therapy in Phase II trials to treat pancreatic and ovarian cancer [241b,c]. Alvocidib (Flavopiridol, HMR 1275, 173) a synthetic derivative of rohitukine 174, isolated from Dysoxylum binectariferum [242a], is being developed by Sanofi-Aventis as their oncology pipeline in collaboration with NCI. Alvocidib 173 is a CDK inhibitor [242b] that prevents phosphorylation of CDKs and by down-regulating cyclin D1 and D3 expression results in G1 cell cycle arrest and apoptosis. As on May 2009, 173 is under late Phase III oncology pipeline by Sanofi-Aventis to use in the treatment of NSCLC patients while in Phase IIb for patients with chronic lymphocytic leukemia [242c]. Curcumin 175, a polyphenol extracted from roots of Curcuma longa (a popular Indian spice of family Zingiberaceae), has been considered significant against metastatic colon cancer due to its ability to interfer with the p53 tumor suppressor pathway [243].

Curcumin 175 is under various world wide Phase I/II trials while a Phase III trial in patients with MCC is underway. RTA 402 (CDDO-Me, Bardoxolone methyl, 176) a synthetic triterpenoid analog of oleanolic acid 177, occurring naturally in various food and medicinal plants [244a], is being evaluated by Reata Pharmaceuticals in under Phase I/II clinical development against prostate cancer and Phase II trials in type 2 diabetes with chronic kidney disease (CKD). RTA 402 176 potently inhibits the activation of IkB alpha kinase (IKK) associated with suppression of nuclear factor kappa-B (NF-kB) dependent genes that prevent apoptosis, promote proliferation and angiogenesis [244b]. In October 2008, an orphan drug designation by the FDA was granted to 176 against prostate cancer. In January 2010, Reata Pharmaceuticals have given exclusive rights to Kyowa Hakko Kirin for development and commercialization of 176 in Japan and other selected Asian regions for treatment of type 2 diabetes suffering from CKD [244c]. Betulinic acid (ALS-357) 68, a pentacyclic triterpenoid isolated from white birch (B. pubescens), was evaluated in preclinical studies by Advanced Life Sciences where it demonstrated specific antitumor activity against malignant melanoma (MM). ALS-357 68 has a unique mechanism of action that disrupts mitochondrial membrane function and is associated with the intrinsic, mitochondria-mediated pathway of apoptosis [245]. ALS-357 68 has orphan drug designation by the FDA for topical treatment of MM and is currently in Phase I clinical development by Advanced Life Sciences. Silybin 178, a flavonolignan extracted from blessed milk thistle (Silybum marianum) and the active constituent of IdB 1060 (silybin-phosphatidylcholine complex, SiliphosÒ), is currently in Phase II clinical development by American College of Gastroenterology for cancer chemoprevention [246]. 8.1.2. Microorganism-derived compounds 8.1.2.1. Actinomycetes. Pladienolide D 179, discovered as bioactive compounds in Streptomyces platensis Mer-11107 fermentation broth, exerts potent antiproliferative activities against a wide variety of cancer cell lines [247a,b]. E7107 180 is a synthetic urethane derivative of 179 that binds with spliceosome-associated protein 130 (SAP130) and inhibits the splicing of pre-mRNA resulting in cell cycle arrest [247c]. Eisai are evaluating 180 in Phase I trials against solid tumors. Chartreusin (U-7257, 181) and elsamicin A (BMY-28090, elsamitrucin, 182) are the antibiotics having similar structures and both inhibit RNA synthesis and result in single-strand scission of DNA. Chartreusin 181 was originally isolated from the culture broth and mycelial cake of Streptomyces chartreuses. Elsamicin A 182 that bears chartarin chromophore but differ in sugar moieties i.e. bears an amino sugar, was isolated from actinomycete strain J907-21 in 1986 [248]. Elsamicin A 182 is also a potent inhibitor of topoisomerase I and II, enzymes that play an important role in DNA replication. Elsamicin A 182 is under Phase II clinical trials by Spectrum Pharmaceuticals for treatment of patients with advance solid tumors. Doxorubicin (AdriamycinÒ) 183, an anthracycline antibiotic originally isolated from bacteria found in soil samples taken from Castel del Monte, an Italian castle, is a DNA intercalating drug commonly used against a wide range of cancers, including hematological malignancies, many types of carcinoma, and soft tissue sarcomas [249a]. L-annamycin 184 was originally developed at the M D Anderson Cancer Center while studies on clinical limitations with anthracycline drugs. Doxorubicin 183 has orphan drug status by the FDA to use in the treatment of acute lymphocytic leukemia (ALL) and AML. L-annamycin 184 inhibits topoisomerase II and is currently in Phase I/IIa trials by Callisto Pharmaceuticals in adults with ALL as well as younger adults with refractory or relapsed ALL or AML [249b]. Berubicin (RTA744, WP744, 185) is an anthracycline

B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807

that intercalates with DNA and inhibits DNA replication by binding with topoisomerase II, is able to cross the blood brain barrier, hence finds significance in the treatment of primary brain tumor. In October 2006, orphan drug designation to 185 was granted by the FDA against malignant gliomas. Reata Pharmaceuticals are currently conducting Phase II clinical trials of 185 for treatment of malignant gliomas. Sabarubicin (MEN-10755, 186), a topoisomerase II inhibitor [250a] and disaccharide analog of 183, is currently in Phase II clinical trial by Menarini Pharmaceuticals against solid tumors [250b,c]. Sabarubicin 186 is also being evaluated as combination therapy with cisplatin against small-cell lung cancer (SCLC). Nemorubicin (MMDX, PNU-152243A, 187) a 30 -deamino-30 [2-(S)-methoxy-4-morpholinyl] derivative of 183, is a DNAintercalator and potent inhibitor of topoisomerase I, shows activity on selected tumors resistant to current treatment. Nemorubicin 187 is currently in Phase I/II trials by Nerviano Medical Sciences [251]. Distamycin A 188 is the lead compound of brostallicin (PNU166196) 189 that was originally developed by Nerviano as a DNA minor grove binder (MGB) which retains sensitivity in DNA mismatch repair-deficient tumor cells [252]. The a-bromoacrylic moiety of 189 appears to reacts with GSH, in a reaction catalyzed by GST, with the possible formation of a highly reactive GSH-complex able to bind covalently to DNA [253]. Nerviano had transferred the exclusive world right of 189 to Systems Medicine Inc. that has now been taken over by the Cell Therapeutics. Cell Therapeutics are currently evaluating 189 in a Phase II trial as monotherapy in patients with advanced or metastatic soft tissue sarcoma (MSTS), and in a context of vulnerability trial in several patient populations [254]. Geldanamycin 190, a benzoquinone ansamycin antibiotic originally discovered in the broth and the mycelium of Streptomyces

4795

species [255a], can bind with heat shock protein 90 (HSP90) playing crucial role in apoptosis, angiogenesis and oncogenesis [255b,c]. Tanespimycin (17-AAG, KOS-953, NSC-330507, 191) is a comparatively less toxic derivative of 190 and exerts anti-melanoma effect by binding to HSP90 and interrupts the MAPK pathway [256]. As on November 2009, a Phase II/III randomized open-label trial of 191 in combination with VelcadeÒ in relapsed-refractory multiple myeloma patients has been completed by Kosan. Alvespimycin (17DMAG, KOS-1022, NSC-707545,192) developed by Kosan as a second generation HSP90 inhibitor [257] is under clinical development for treatment of solid tumors. As of January 2008, 192 is being evaluated as combination therapy in a Phase I trial with trastuzumab & paclitaxel (TaxolÒ) against solid tumors, Phase II trial as monotherapy against HER2-positive metastatic breast cancer and Phase I trial against solid tumors. Retaspimycin (IPI-504, 17-AAG hdroquinone salt, 193) is a HSP90 inhibitor that is under Phase I/II clinical development by Infinity Pharmaceuticals as a single agent and in combination with existing drugs against certain cancers [258]. Infinity is currently conducting a Phase II clinical trial of 193 in NSCLC patients, while also enrolling patients for another Phase II trial to evaluate 193 in combination with HerceptinÒ in patients with HER2 positive metastatic breast cancer [259]. The mTOR inhibitor, deforolimus (AP23573, MK-8669, 194) is being co-developed by Merck and ARIAD Pharmaceuticals for the treatment of several tumor types including sarcoma [260]. In May 2009, ARIAD have changed the name of 194 form ‘deforolimus’ to ‘ridaforolimus’, and the same was adopted by the United States Adopted Name (USAN) Council. Ridaforolimus 194 has fast-track and orphan drug designation by the FDA and orphan drug status by the EMEA against soft tissue and bone sarcomas. In December 2009, ARIAD Pharmaceuticals completed the enrollment for

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a Phase III study of oral 194 in patients with metastatic soft tissue and bone sarcomas. Besides, ARIAD are also running several Phase I/II trials to evaluate 194 as a single agent and in combination therapies [261]. Salinosporamide A (NPI-0052, 195), possessing a g-lactam-blactone bicycle is produced by a marine bacterium Salinispora tropica [262a]. Salinosporamide A 195 is a proteasome inhibitor that exerts activity by modifying the threonine residues of the 20S proteasome [262b]. In May 2006, 195 entered Phase I clinical trials by Nereus against solid tumors and lymphomas. As on April 2008, Nereus Pharmaceuticals are enrolling patients for a Phase Ib trial of 195 in combination with vorinostat (ZolinzaÒ) for selected solid tumor malignancies [262c]. Staurosporine 196, an alkaloid originally isolated from bacterium Streptomyces staurosporeus [263a], is the precursor of protein kinase inhibitors [263b], enzastaurin (LY317615) 196 and midostaurin (PKC-412, CGP 41251, 40 -N-Benzoyl-staurosporine) 198. Enzastaurin (LY317615, 197) is a serine/threonine kinase inhibitor and is under clinical development by Eli Lilly for treatment of variety of tumor types [264]. In June 2007, Eli Lilly announced the results of a Phase II clinical trial of 197 in patients with late-stage NSCLC. As of April 2010, 197 is under Phase III trials against diffuse large B-cell lymphoma (DLBCL) [265]. Midostaurin 198 was demonstrated safe in Phase I pharmacokinetic study by Novartis

[266]. PKC-412 198 inhibits several protein kinases including FLT3 and is highly anticipated as a potent therapeutic agent for Phase II trials in AML patients carrying FLT3 mutations. K252a 199, an alkaloid isolated from soil fungi of Nocardiopisis species, is a staurosporine analog and the lead compound of lestaurtinib (CEP-701, KT-5555, 200) that inhibits FLT3 [267a] and tyrosine phosphorylation of Trk A. As of 2008, lestaurtinib 200 is in Phase III clinical trials for AML and Phase II trials for myeloproliferative disorders. In June 2009, Cephalon disclosed the results from a pivotal trial of 200 in patients with relapsed AML expressing FLT3 mutations [267b]. Another staurosporine analog, KRX-0601 (UCN01, KW-2401, 201) inhibiting CDKs, is currently in Phase II clinical trials by Keryx (Kyowa Hakko) under sponsorship of NCI for treatment of melanoma, TCL and SCLC [268]. Diazepinomicin (ECO-4601, TLN-4601, 202) is a dibenzodiazepine alkaloid originally isolated from the culture of a marine actinomycete of the genus Micromonospora [269] that binds selectively to peripheral benzodiazepine receptor (PBR), resulting in tumor apoptosis, and inhibits the Ras/MAP kinase signaling pathway involved in cellular proliferation and migration [269c]. ECO-4601 202 was found safe and well-tolerated in Phase I/II trial conducted by the NCI and Thallion. In November 2007, Thallion demonstrated that 202 can cross the blood brain barrier and targets glioblastoma multiforme (GBM). As on September 2008, Thallion

B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807

are enrolling patients for Phase II trial of 202 as a second line treatment for GBM [269d]. 8.1.2.2. Eubacteria. Prodigiosin (Streptorubin B, 203), a red pigment produced by many strains of the bacterium Serratia marcescens [270] and is the lead compound of obatoclax (GX15-070, 204), a Bcl-2 inhibitor that is under clinical development by Gemin X for treatment of tumors. Gemin X are developing intravenous infusion of 204 in multiple Phase I/II trials as a monotherapy in hematological and solid tumor cancer indications while as combination therapy with carboplatin & etoposide in SCLC and with bortezomib (VelcadeÒ) in mantle cell lymphoma (MCL). In March 2009, Gemin X launched a Phase II study of 204 in combination with carboplatin & etoposide as first-line treatment SCLC while results of a Phase Ib trial of 204 as first line treatment for extensivestage SCLC was release in May 2009 [271]. 8.1.2.3. Myxobacteria. Patupilone (epothilone B, EPO-906, 21), microtubule-stabilizing NP produced by the myxobacterium S. cellulosum, is currently under Phase III trials by Novartis against ovarian cancer while Phase II clinical development for the treatment of other tumor types [272]. Sagopilone (ZK-EPO, ZK-219477, 205) is a synthetic derivative of 21 that binds to tubulin and induces microtubule polymerization [273a] causing inhibition of cell division, induction of G2/M arrest, and apoptosis [273b]. Unlike taxanes, 205 is able to retain activity in MDR cancer cells overexpressing the P-gp. As of February 2010, ZK-EPO 205 is in Phase II clinical development by Schering AG against lung, ovarian and prostate cancers [273c]. Epothilone D (desoxyepothilone B) 206 is a natural polyketide that inhibits the disassembly of microtubules by binding to tubulin. The 9,10-didehydroepothilone D (KOS-1584, 207) [274], a second-generation epothilone derivative of 206 being evaluated by Kosan Pharmaceuticals in multiple solid tumor types. In Phase I dose escalation trials by Kosan, 207 has defined efficacy and tolerability against patients with ovarian cancer and NSCLC. As of

4797

February 2007, Kosan were planning to initiate Phase II clinical development of 207 against multiple solid tumors in collaboration with Roche. 8.1.2.4. Fungi. NPI-2350 (halimide, phenylahistin, 208), a diketopiperazine metabolite consisting of L-phenylalanine and isoprenylated dehydrohistidine, was originally isolated from a marine fungi aspergillus ustus. Plinabulin (NPI-2358, 209), a tubulindepolymerizing synthetic analog of 208 [275a], is under clinical development by Nereus. In November 2009, Nereus announced the positive results of a Phase II trial of 209 as combination therapy with docetaxel in NSCLC patients [275b]. Irofulven (MGI-114, HMAF, 210), an analog of illudin S 211, a sesquiterpene toxin found in mushrooms of the genus Omphalotus [276]. Irofulven 210 inhibits DNA synthesis and is currently in Phase II/III development by Eisai (MGI Pharma) in patients with advanced-stage prostate cancer and advanced GI solid tumors. 8.1.3. Marine-derived compounds Plitidepsin (AplidinÒ, 212), a cyclic depsipeptide extracted from Aplidium albicans, is being evaluated in Phase II clinical trials by PharmaMar in hematological and solid tumors. Plitidepsin 212 inhibits the vascular endothelial growth factor (VEGF) protein that causes vascularization and growth of tumors. After getting promicing results from a multicenter Phase Ib study, PharmaMar are currently evaluating 212 under Phase II trials as a first-line monotherapy treatment and in combination with dacarbazine for advanced unresectable melanoma [277]. Halichondrin B 213, isolated from Halichondria okadai sponge [278a], has been considered significant by NCI as a novel anticancer agent. Eribulin mesylate (E7389, ER-086526, NSC-707389) 214, a structurally-simplified and pharmaceutically-optimized analog of 213, is being developed by Eisai as a third-line treatment against advanced breast cancer patients, previously treated with standard cancer chemotheraputics. Eribulin 214 is a microtubule dynamics inhibitor that prevents various cellular processes [278bed]. In

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OCH3H C 3 N H

OCH3

N

N H

N

HN 204

203

HN

CH3

H3C

O

S

CH3

CH3

H3C

H3C N

H3C CH3 H3C

O

OH

OH H3C

OH

OH

O

CH3

O O

O

OH H3C

NH

CH3

H3C

O

CH3 NH

N

HN H3C

H3C

208

CH3

O

NH

CH2

CH3 OH

207

N

HN

O

O

CH3

206

N

CH3 O

205 S

CH3

H3C

CH2 O

H3C

O

O

N

S

NH CH3 CH3

CH3

HO H3C

209

March 2010, Eisai submitted regulatory applications to agencies in Japan, US and EU for approval of 214 against locally advanced or metastatic breast cancer. Hemiasterlin 215, a NP-derived from marine sponges [279], inhibits tubulin assembly and disrupts normal microtubule dynamics and depolymerizes the microtubules. E7974 216, a synthetic analog of 215 that can bind to a and b tubulin, is under Phase I clinical development by Eisai against a variety of human tumor xenografts. Psammaplin A 217, isolated from the marine sponge Psammaplinaplysilla, inhibits the key enzymes that control gene expression, DNA replication and angiogenesis. Panobinostat (LBH-589, 218) a synthetic analog of 217 is being evaluated by Novartis in Phase I as a single agent therapy in several tumor types [280a]. Panobinostat 218 is a pan-deacetylase inhibitor and induces death of tumor cell lines but not the normal cells [280b]. Panobinostat 218 is currently in Phase Ib/II clinical trils as monotherapy and in combination with chemotherapy and/or targeted therapy against Hodgkins lymphoma, MM, AML/MDS and other hematological malignancies while global enrollment for Phase III trial in relapsed MM is underway. Bryostatin 1 219, a macrolide lactone first isolated from extracts of a species of bryozoan, Bugula neritina collected in the Gulf of California and Mexico, exerts antineoplastic activity by inhibiting PKC [281a]. Bryostatin 1 219 has orphan drug status granted by the

OH

O 210

CH3

CH3

CH3 OH

HO H3C

OH

O 211

FDA (2001) and a similar designation by the EU (2002) for use in combination with TaxolÔ against esophageal cancer. In 2001, the 219 was licensed by GPC Biotech from Arizona State University and is currently in various Phase I/II trials under guidance of the NCI [281b,c]. Jorumycin 220, first isolated from the nudibranch Jorunna funebris [282a], is the lead compound of ZalypsisÒ (PM00104/50) 221 that was evaluated in Phase I clinical trials by PharmaMar against solid tumors or lymphoma. ZalypsisÒ 221 exerts cytotoxic effects dependent on DNA binding that are not associated with DNA damage. As on November 2009, 221 is in Phase II clinical trial for treating cervical cancer as well as endometrial cancer patients previously with standard chemotherapy [282b]. Dolastatin 15 222, a seven-subunit depsipeptide derived from Dolabella auricularia, is a potent antimitotic agent structurally related to the antitubulin agent dolastatin 10 224, a five-subunit peptide obtained from the same organism [283]. Although first isolated from a sea hare D. auricularia, the dolastatins (222 & 224) have cynobacteria origin. Tasidotin (synthadotin, ILX-651, 223), a third-generation analog of 222 that induces G2/M phase cell cycle arrest by inhibiting tubulin polymerization in vitro similar to the vinca alkaloids [284a], was evaluated by Genzyme in Phase I/II trials against solid tumors [284b]. In May 2009, Genzyme signed an agreement with Ergomed for the co-development of 223 as an

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antineoplastic agent. Soblidotin (YHI-501, TZT-1027, auristatin PE, 225), a derivative of 224 that inhibits tubulin polymerization, resulting in G2/M phase cell cycle arrest and apoptosis, [284c] is under Phase II clinical development by Yakult Honsha for treatment of solid tumors. Kahalalide F 226, a depsipeptide that alters lysosomal membrane function was originally extracted from the Hawaiian sea slug Elysia rufescens [285a]. Kahalalide F 226 alters lysosomal membrane function, and as of October 2008 it is in Phase II trials

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against severe psoriasis. Various other Phase II clinical trials for 226 in melanoma, NSCLC and hepatocarcinoma are still running. In June 2009, PharmaMar licensed 226 to Medimetriks Pharmaceuticals for uses other than oncology and neurology [285b]. PM02734 (IrvalecÒ, 227) is another derivative of 226 being evaluated in Phase II development by PharmaMar against solid tumors. As on February 2010, PharmaMar are recruiting for a Phase I study of 226 as combination therapy with erlotinib against advanced malignant solid tumors.

OCH3 H3C

CH3

O

O

N

NH O

H3C H3C

O

N O H3C O OH

O

O CH3

H3C

O

HO O

H HO H3C O H HO

O NH2

O

N

O

O

H

CH3 H

H

H

H

H

O

213

H

H2C

H

O

O

O

O

CH2H O CH3 O

O

H

O H CH2 O O CH3

O

OH

O

CH3

O

H

O O

O

H CH3

O

O

CH3

H

O

N O

212

H

CH3

N H NH H C 3 CH3

CH3 H H O

CH3

O

H3C

O

OH

3

HN

N

O

H3C CH O

H3C

CH3 CH3 CH3 N

N H

CO2H CH3 CH3

O H3C

CH3

215

Br H2C

214

O CH3 H3C CH3 H C CH3 3 O CH3 N H N N CO2H N N HO H CH3 O CH3 H3C O 216 OH N H H O N HN

CH3

S

H N

S 217

O

OAc O

O O

O HO HO O

OCH3 219

H3C

OH

OH

Br

H3C H3C HO

H3C

218

N

OH H3C

CH3 O O

OCH3 O

4800

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8.2. NPeantibody anticancer conjugates During the last few decades, conjugation of potent anticancer agents to various supports such as antibodies, polymers, liposomes and nanoparticles for anticancer drug delivery has been extensively explored, hoping to improve the efficacy and to reduce side effects of chemotherapy. Certain kind of anticancer drug nanovectors have been developed to target tumors [286a]. Zinostatin stimalamer (ZSS), synthesized by conjugation of one molecule of neocarzinostatin (NCS) chromoprotein and two molecules of poly(styrene-co-maleic acid), was first polymer-based anticancer agent launched by Yamanouchi (now Astellas) in Japan for the treatment of hepatocellular carcinoma. Gemtuzumab ozogamicin

4801

(MylotargÒ) 228, a humanized anti-CD33 antibody linked to calicheamicin 229 [286b,c], a cytotoxin enediyne antibiotic derived from the bacteria Micromonospora echinospora, was the first and only approved antibody-anticancer conjugate co-developed by Wyeth and UCB Pharma. Another calicheamicin-antibody conjugate, inotuzumab ozogamicin (CMC-544) having the same CalichDMH and hydrazone linker attached to humanized IgG4 anti-CD22 [287], is being developed by Wyeth and UCB Pharma. CD22 is a B-lymphoid lineage-specific differentiation antigen that undergoes rapid internalization upon binding and delivers the conjugated CalichDMH inside the cancer cells. Inotuzumab ozogamicin is under Phase II/III trials against non-Hodgkin’s lymphoma as combination

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therapy with rituximab, a chimeric human IgG1 antibody that targets another B-lymphoid lineage-specific molecule, CD20. Maytansine 230, a macrolide isolated from plants of the genus Maytenus, inhibits the assembly of microtubules by binding to tubulin at the rhizoxin binding site. Maytansine 230 despite

positive Phase I/II trials in the 1970s, failed to show significant efficacy at non-toxic concentrations. To exploit the anticancer potential of these compounds ImmunoGen introduced new maytansinoid-antibody conjugates [288], e.g., IMGN-242 (HuC242-DM4, 231), a conjugate of the cytotoxic

Table 2 Halted or discontinued NP’s in oncology [16]. Lead and source Plant Camptothecin 133 Paclitaxel 148

Vinblastine 146 Microorganism Doxorubicin 183 Spicamycin Rebeccamycin (staurosporine 196) Epothilone D 206 Patupilone 21 Fumagillin 3 Marine Hemiasterlin 215 Squalamine 118 Dolastatin 10 224

Name (synonym)

Mechanism of action

Comment

Rubitecan (OrathecinÔ, 9-NC) BMS-184476 BMS-275183 TL-310 Simotaxel(MST-997, TL-909) (HydravinÔ, KRX-0403)

Topoisomerase I Tubulin stabilization Tubulin stabilization Tubulin stabilization Tubulin stabilization Tubulin binding

SuperGen discontinued development No update by BMS Phase II trials halted by BMS Not on clinicaltrials.gov Phase I trials terminated (Wyeth/Taxolog) Keryx discontinued

Galarubicin (DA-125) KRN-5500 89 Edotecarin (J-107088) XL-119, NSC 655649, BMY-27557 KOS-862 207 ABJ879 BMS-310705 CKD-732 PPI-2458

Topoisomerase II inhibition DNA synthesis inhibitor Topoisomerase I Topoisomerase II Tubulin stabilization Tubulin stabilization Tubulin stabilization MetAP2 inhibition MetAP2 inhibition

Not listed on Dong A pipeline Discontinued by Kirin Brewery Discontinued in 2005 by Pfizer Helsinn Healthcare discontinued Discontinued by Kosan and Roche Not in Novartis’s pipeline Not listed in BMS’s pipeline No update by Chong Kun Dang GSK terminated the trial

HTI-286 (SPA-110) Squalamine 118 Dolastatin-10 224

Tubulin assembly inhibition NHE-5 inhibition Tubulin assembly inhibition

Discontinued by Wyeth in 2005 Trials discontinued by Genaera Discontinued by NIH

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maytansinoid DM4 and the monoclonal antibody huC242 through a disulfide linker, was developed and evaluated by ImmunoGen as a targeted therapy in Phase II trials for CanAg-expressing cancers, including gastric cancer. In June 2009, ImmunoGen discontinued further internal development of 231 and shifted it to out-licensing portfolio. ImmunoGen are also evaluating IMGN-901 (HuN901DM1, 232), a conjugate of maytansinoid DM1 and huN901 that target CD56 expressing tumors is in a Phase II trial against SCLC and a Phase I trial for multiple myeloma. An orphan drug designation was given to 232 by FDA in March 2010 for the treatment of merkel cell carcinoma (MCC). 8.3. Halted or discontinued compounds in oncological diseases Compounds for which clinical trials in oncology have been halted or discontinued since 2005 are listed in Table 2. 9. Conclusion NP scaffolds are infact key in drug discovery and in optimizing chemical diversity for human use. The abundant scaffold diversity in NPs is coupled with ‘purposeful design’ e usually to afford an advantage for survival in environments threatening growth and/or survival of producer orgainsm. It is reasoned that these ecological defense systems, produced to combat competing life forms, would have some biological activity that gives the producer organism an advantage. The quality of leads arising from NP discovery is better and often more biologically friendly, due to their co-evolution with the target sites in biological systems. The large number of NP-derived compounds in various stages of clinical development indicates that the use of NP templates is still a viable source of new drug candidates. The traditional strengths of NPs in oncological and infectious diseases are still ahead from the compounds under clinical trials against metabolic and other diseases. Acknowledgments Financial assistance from Department of Science & Technology, India has gratefully been acknowledged. References [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23]

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