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hetero Diels–Alder reaction and their cytotoxicity evaluation
Bioorganic & Medicinal Chemistry Letters xxx (2014) xxx–xxx
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Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl
Synthesis of novel chromeno-annulated cis-fused pyrano[3,4-c]benzopyran and naphtho pyran derivatives via domino aldol-type/hetero Diels–Alder reaction and their cytotoxicity evaluation Jyothi Madda a, Akkaladevi Venkatesham a, Naveen Kumar Bejjanki a, Nagaiah Kommu a,⇑, Sujitha Pombala b, C. Ganesh Kumar b, Tadikamalla Prabhakar Rao c, Jagadeesh Babu Nanubolu d a
Division of Organic and Biomolecular Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India c Center for Nuclear Magnetic Resonance, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India d X-ray Crystallography Laboratory, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India b
a r t i c l e
i n f o
Article history: Received 28 March 2014 Revised 14 July 2014 Accepted 4 August 2014 Available online xxxx Keywords: Chromeno pyrano[3,4-c]benzopyran and naphtho pyrans Aldol-type/hetero Diels–Alder reaction cytotoxicity evaluation HeLa (cervical) MDA-MB-231 (breast) MCF-7 (breast) A549 (lung)
a b s t r a c t New chromeno-annulated cis-fused pyrano[3,4-c]benzopyran and naphtho pyran derivatives have been synthesized by domino aldol-type reaction/hetero Diels–Alder reaction generated from o-quinone methide in situ from 7-O-prenyl derivatives of 8-formyl-2,3-disubstituted chromenones with resorcinols/ naphthols in the presence of 20 mol % ethylenediamine diacetate (EDDA), triethylamine (2 mL) as co-catalyst in CH3CN under reflux conditions in good yields. The structures were established based on spectroscopic data, and further confirmed by X-ray diffraction analysis. The results showed that compounds 4h and 4j exhibited very potent cytotoxicity against human cervical cancer cell line (HeLa). Compound 4h displayed good inhibitory activity against both breast cancer cell lines, MDA-MB-231 and MCF-7. Further, the compound 4i exhibited good cytotoxicity against only MDA-MB-231, and compound 4j showed promising activity against human lung cancer cell line, A549 with IC50 value of 2.53 ± 0.07 lM, which was comparable to the standard doxorubicin (IC50 = 1.21 ± 0.1 lM). Ó 2014 Elsevier Ltd. All rights reserved.
Today, cancer posses one of the most serious health problems, that is difficult to treat due to the successive mutations on oncogenes and suppressor genes that deregulate the cell cycle.1 In recent years, combination of novel heterocyclic compounds and understanding the biology of cancer has been exceptionally improved anticancer activity2 by connecting with novel mechanisms, such as carcinogens inactivation, antiproliferation, cell cycle arrest, induction of apoptosis and differentiation, inhibition of angiogenesis, antioxidation and reversal of multidrug resistance.3 Now a days, many classes of drugs are being used for the treatment of cancer which have developed resistance in cancer therapy4 and unable to differentiate between normal and neoplastic cells or to overcome primary or secondary resistance mechanisms evolved in the cancer cells. Thus, there is a vital need for identifying new anticancer agents with high potency by preventing cancer cell proliferation, less toxicity in non-cancerous cells, and unique targets of ⇑ Corresponding author. E-mail address: [email protected] (K. Nagaiah).
action is still not precluded. In recent years, chromenopyrano/pyranopyrans containing heterocyclic synthesis has attracted tremendous interest among researchers due to their potential applications in medicinal chemistry (Fig. 1).5 2,2-Dimethylbenzopyran template, a structural motif found in numerous natural products, which have potential applications in medicine.6 This functionalized moiety exhibits diverse biological activities such as anticancer activity,7,8 anti-HIV activity,9 insecticidal,10 antifungal activity,11 potassium channel activators,12 aldosterone biosynthesis inhibitors,13 5-hydroxytryptamine-3 receptor antagonist,14 phosphodiesterase IV inhibitor,15 ampicillin-derived antibacterial agent,16 psychotropically active leukemia17 and solid tumor cell lines.18 On the other hand chromeno fused pyranopyran derivatives exhibit significant biological activities such as anti-tumour,19 anti-mycobacterial20 and antiviral activity.21,22 A single molecule containing more than one pharmacophore, each with different mode of action, is beneficial for the treatment of cancer.23,24 Implementation of these approaches in our research group, resulted in the design and synthesis of new hybrid molecules by
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coupling 2,3-disubstituted chromenopyrans and 2,2-dimethylbenzopyran or 2,2-dimethyl naphtho pyran with high stereo specificity. The present study is in continuation to our earlier efforts25 on the synthesis of biologically important compounds using the domino aldol-type/hetero Diels–Alder reaction and the importance of 2,2-dimethylbenzopyran or 2,2-dimethyl naphthopyran and chromenopyrano moieties. We prepared a new series of chromeno-annulated cis-fused pyrano[3,4-c]benzopyran and naphtho pyran derivatives in good yields and with excellent stereo selectivity and investigated their cytotoxicity against a panel of four different cancer cell lines, namely, MDA-MB-231, MCF-7, HeLa, and A549. Requisite 7-O-prenyl derivatives of 8-formyl-2,3-disubstituted chromenones were prepared from 2,3-disubstituted-7hydroxychromeno aldehydes in analogy to our previous work.25 Initially, the domino aldol-type/hetero Diels–Alder reaction, generated from o-quinone methide in situ from 7-O-prenyl derivatives of 8-formyl-2,3-dimethyl chromenones with resorcinol 2a or naphthol 2e in the presence of 20 mol % ethylenediamine diacetate (EDDA)26 and triethylamine (TEA; 2 mL) as co-catalyst in CH3CN at
O OMe MeO H
O O
O
O
O O
O H
O
O
O OH
deguelin
O
O
O O
morusin
HO
R O O
O R=H R = CH 2CH 3
OH O H
HO
O
OH
O
H O
OMe
O O
O
OMe OMe
OCH3
Lonchocarpusone
Calyxin J & Epicalyxin J
Figure 1. Chromeno fused pyrano/pyranopyran heterocyclic natural products.
O
O
H HO
R3
OH
H
O
O OH R1
R3
CHO O
O
R1 R2
+
O 2a: R3 = ethyl, 2b: R3 = methyl, 2c: R3 = benzyl, 2d: R3 = phenyl
R2 O 4a-j cis isomer only 80-90%
EDDA (20 mol%), TEA, CH3CN, 80-85 οC, 12 h
O H
O 1a: R1, R2 = CH 3 1 2 1b: R = H; R = CH 3 1c: R1 = CH 3; R2 = Ph
OH H
O
O
R1 R2
2e
O 4k-l cis isomer only 88-90%
Scheme 1.
Table 1 Optimization of the catalyst EDDA and solvent conditionsa on the reaction of 7-O-prenyl derivative of 8-formyl-2,3-dimethylchromen-4-one (1a) with resorcinol (2a) O CHO O
CH 3
H O
HO
CH3
OH
reagents and conditions
+ CH3 O 1a
H
O
CH3
O O OH CH 3
O
CH 3
2a
4a
O
Solvent
Catalyst (mol %)
Time (h)
Yieldb (%)
Xylene Xylene Xylene Toluene Toluene Toluene CH3CN CH3CN CH3CN CH2Cl2 CHCl3
5.0 10.0 20.0 5.0 10.0 20.0 5.0 10.0 20.0 20.0 20.0
12 12 12 12 12 12 12 12 12 12 12
50 63 70 20 28 42 50 64 78 12 20
Values in bold were measured under optimized best conditions. a Reagents and conditions: 1a (1.0 mmol), 2a (0.66 mmol), triethylamine (2 mL) and solvent (5 mL). b Isolated and unoptimized yields.
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O
CH3
HO CHO O
O
HO
CH 3 +
OH
O
O H 3C
O O CH3
O TEA
CH 3 1a
HO EDDA
CH3 2a
3
O
O
O CH 3
O
O
CH 3
OH O CH3
H 3C
CH3
H 3C
-H2O O
OH O
O
O End o-E-syn II
Exo-Z-syn I
O
O
H
H
CH3
CH3 H O
O
H
O O OH CH 3
O
O O OH CH 3 CH3
CH3 O 4a major trans isomer only
O 4a major cis isomer only
Scheme 2. Explanation of the observed stereochemistry.
O
O
O
HO
CH 3 +
OH
O
O
O
H 3C
CH3
EDDA, TEA -H 2O
CH3 1a
CH 3
O
CHO
2a
H 3C H3C
O
OO
O
O H
O OH H 3C
H3C
O End o-E-syn II Intra molecular hydrogen bonding
O End o-E-syn III No Hydrogen bondings
O
O
OH H
H
CH 3
CH 3 O
H O
O CH 3
CH 3 O 4a 1 major cis isomer only
O
H
O O OH CH 3
CH 3 O 4a major cis isomer only
Scheme 3. Explanation of the observed regiochemistry.
80–85 °C afforded the corresponding cis-fused pyrano[3,4-c]benzopyran/naphtho pyran derivatives 4a and 4k in 85% and 90% yields, respectively, with cis selectivity (Scheme 1). Furthermore, a systematic study was carried out for catalytic evaluation of EDDA for the reaction of 7-O-prenyl derivative of 8formyl-2,3-dimethylchromen-4-one 1a with resorcinol 2a under different solvent conditions with different catalytic loads. As shown in Table 1, different mol % of EDDA (5, 10 and 20) along with triethylamine as co-catalyst, were screened with various solvents like xylene, toluene, acetonitrile, dichloromethane and chloroform at reflux conditions, suggested that EDDA (20 mol %) provided a better yield. The effect of solvents was also examined, and CH3CN was identified as an optimal solvent.
The reaction proceeded via a domino aldol-type/hetero Diels– Alder reaction pathway. This reaction was highly stereoselective affording exclusively cis-fused pyrano[3,4-c]benzopyran and naphtho pyran derivatives (Scheme 2). These results could be explained nicely by assuming that the reactions were governed by stereo electronic and steric effects.27 Thus significantly, the stereo specificity of the formation of the major cis product 4a could be explained by a stereo electronic effect via an endo-E-syn-transition state (II) as shown in Scheme 2. At first instance, 7-O-prenyl-8-formyl-2, 3-dimethyl chromenone 1a reacted with resorcinol 2a in the presence of EDDA, triethylamine as co-catalyst to afford intermediate 3 as an aldol product, which underwent dehydration followed by intramolecular hetero
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(A)H C (B)H 3C3 O Hc Hd
O CH 3
Hb O
Ha
O OH CH 3 O
4e
Figure 2. Characteristic NOE and energy-minimized structure of 4e.
Diels–Alder reaction. The o-quinone methide may potentially follow two pathways for the hetero-Diels–Alder reaction in which the endo-E-syn-transition state (II) might have been more favorable than the exo-Z-syn transition state (I) due to an sp2-geminal effect, according to the phenomenon of 1,3-allylic strain, which had been already proved by Tietze’s work,28 to afford the cisadduct 4a exclusively. In addition, the regiospecificity of the major product 4a formation over 4a1 could be explained as shown in Scheme 3. Accordingly, the interaction of the resorcinol 2a with 7-O-prenyl derivatives of 8-formyl-2,3-dimethyl chromenones 1a by aldol reaction followed by dehydration to form two possible o-quinone methide intermediates 4a and 4a1 in endo-E-syn fashion. The o-quinone methide adduct 4a was favourable heterodiene than 4a1. This selectivity could be explained by the deactivation of the o-OH group by an intramolecular hydrogen bonding29 with the neighbouring carbonyl group, as confirmed by 1H NMR analysis of 4a, in which a singlet peak corresponding to the o-OH proton was observed at d 13.1 ppm. The stereo- and regio-selectivity of the investigated hetero Diels– Alder reactions carried out in this work were similar to those of earlier reported intermolecular analogues.30 The stereochemistry of the product 4e was assigned on the basis of 1H NMR J-coupling constants and NOE studies. In the 1H NMR spectrum, the vicinal coupling constant JHa–Hb = 5.2 Hz in between Ha (d 4.71 ppm) and Hb (d 2.21 ppm) indicated an equatorial and axial orientation of these protons, respectively, in a chair conformation, which confirmed that the two six membered tetra hydropyran rings were cis-fused. In addition, the observed vicinal coupling constants like JHb–Hc = 5.2 Hz, JHb–Hd = 11.3 Hz and x coupling of JHa–Hc = 1.5 Hz, confirmed the positions of Ha, Hb, Hc, and Hd as shown in Figure 2. The presence of NOE correlations between Ha/Hb, Hb/Hc, Ha/Me-A and Hb/Me-A and Me-B further supported the above observation. The energy-minimized structure of 4e was in full agreement with the above NMR analysis (Fig. 2). Further, the stereochemistry was also assigned by COSY and HSQC studies. Moreover, the spatial stereochemistry of the product 4a was also confirmed by single crystal X-ray diffraction (CCDC deposition
number 905891). It represented that the asymmetric unit was consisting of two molecules with a single molecular structure (Fig. 3). To investigate the scope of EDDA-catalyzed synthesis of chromenoannulated cis-fused pyrano[3,4-c]benzopyran and naphtho pyran derivatives, several o-quinone methides (derived in situ from resorcinols or naphthols and 7-O-prenyl derivatives of 8-formyl2,3-disubstituted chromenones in CH3CN) were examined under similar reaction conditions and the results were summarized in Table 2. Thus, we synthesized a novel series of chromeno-annulated cisfused pyrano[3,4-c]benzopyran and naphtho pyran derivatives (4a–l) in good to excellent yields and all the products were new and characterized by 1H NMR, 13C NMR, IR and mass spectroscopic techniques. The inhibitory efficiency (IC50 values) was tested for all the synthesized chromeno-annulated cis-fused pyrano[3,4-c]benzopyran and naphtho pyran derivatives against a panel of four different cancer cell lines such as MDA-MB-231, MCF-7, A549 and HeLa. The MTT assay was performed by following the previously reported protocol in a 96 well plate.31 Results of the in vitro anticancer activity were compared with the reference drug, Doxorubicin. Further, the active compounds 4h–j did not exhibit any cytotoxicity on HEK293 cell line derived from human normal embryonic kidney cells. Table 3 showed the IC50 values of chromeno-annulated cis-fused pyrano[3,4-c]benzopyran and naphtho pyran derivatives against different cancer cell lines and some of them displayed improved activity as compared to the standard Doxorubicin. Specially, the compound 4h exhibited promising cytotoxicity against different cell lines such as HeLa, MDA-MB-231 and MCF-7 and further it was 3fold less potent (IC50 = 1.5 ± 0.08 lM) than Doxorubicin (IC50 = 0.45 ± 0.07 lM), while 4i and 4j showed good cytotoxicity selectively against MDA-MB-231 and HeLa, respectively. Further, compound 4j also displayed selective cytotoxicity and was 2-fold less potent (IC50 = 2.53 ± 0.07 lM) than doxorubicin (IC50 = 1.21 ± 0.1 lM), against A549 cell line. Our efforts to understand the structure-activity relationship of the lead compound 4h showed broad cytotoxicity against HeLa, MDA-MB-231 and MCF-7 cell lines, which suggested the presence of phenyl substitution on the carbonyl group and also the presence of mono methyl substituent on the chromenone moiety. In addition, in case of compounds 4i and 4j the basis of cytotoxicity was due to the presence of ethyl and methyl substituents on the carbonyl group, respectively, and also the existence of phenyl and methyl substituents on the chromenone moiety. In general, it was observed that the compounds with 3-methyl, 2-phenyl, and only 2-methyl substitutions on the chromenone moiety seems to exhibit promising cytotoxicity as compared to the presence of 2, 3-dimethyls on the chromenone moiety.
Figure 3. ORTEP diagram for the compound 4a, with displacement ellipsoids drawn at 30% probability level.
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J. Madda et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx Table 2 EDDA catalyzed synthesis of chromeno-annulated cis-fused pyrano[3,4-c]benzopyran and naphtho pyran derivativesa Entry
Aldehyde type
Productb (4a–l)
Resorcinol type HO
CHO O
O
OH
O
CH3 CH3
O
Yieldc (%)
12
85
12
86
12
88
12
90
12
80
12
81
12
82
12
88
12
83
O
H
CH 3
CH 3
a
Time (h)
H
O
O OH CH3
O CH3 O HO
CHO O
O
b
OH
CH3
O
O
CH3
O
H
CH 3
CH3 H
O
O OH CH
3
O CH3 O HO
CHO O
O
OH
O
CH 3
O
H
Ph
Ph CH 3
c
O
H
O
O OH CH3
O CH3 O CHO
HO
O
O
d
OH
CH 3
O
CH 3
O
H
Ph
Ph H
O
O
O OH CH3
O CH3 O CHO
HO
O
OH
O
O
CH3
CH 3
e
O
H O
CH3
H
O
O OH
O CH3 O CHO
HO
O
OH
O
f
O CH3
CH3
CH 3 H
O
O
O
H O OH
O CH3 O CHO
HO
O
OH
O
O
Ph
Ph
g
O
H CH3
H
O
O
O OH
O CH3 O
CHO O
HO
OH
O
h
O
O
CH3
O
H
Ph
Ph H
O
O OH
O CH 3 O CHO O
HO O
OH
O
CH3 CH3 Ph
i
O
H O
O
CH3 H
O OH CH 3
O Ph O
(continued on next page)
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Table 2 (continued) Entry
Aldehyde type
Productb (4a–l)
Resorcinol type HO
CHO O
O
OH
CH 3 O
Ph
j
O
Yieldc (%)
12
83
12
90
12
88
O
H
CH 3
Time (h)
CH3 H
O
O OH CH 3
O Ph O CHO O
OH O
CH 3
O H
CH 3
k
O
H
O
O
CH 3 CH 3
O CHO O
OH O
O CH 3
l
O
O
H
O CH 3 O
a b c
Reagents and conditions: aldehyde 1 (1.0 mmol), resorcinol or naphthol 2 (0.66 mmol), EDDA (20 mol %), triethylamine (2 mL) and solvent (5 ml), 80–85 °C. All product were characterized by 1H, 13C NMR, IR and mass spectroscopic techniques. Isolated yields.
Table 3 Cytotoxicity evaluation of compounds 4a–la Compound (lg mL
4a 4b 4c 4d 4e 4f‘ 4g 4h 4i 4j 4k 4l Doxorubicin
1
IC50 values (in lM)
) HeLa
MDA-MB-231
MCF-7
A549
>100 >100 >100 >100 >100 >100 >100 1.5 ± 0.08 18.19 ± 0.25 4.81 ± 0.13 >100 >100 0.45 ± 0.07
>100 >100 >100 >100 >100 >100 >100 5.68 ± 0.13 6.15 ± 0.09 46.8 ± 0.59 >100 >100 0.50 ± 0.06
>100 >100 >100 >100 >100 >100 >100 6.24 ± 0.19 20.5 ± 0.65 11.23 ±0.27 >100 >100 1.05 ± 0.09
>100 >100 >100 >100 >100 >100 >100 16.98 ± 0.27 19.26 ± 0.98 2.53 ± 0.07 >100 >100 1.21 ± 0.1
Values in bold indicate that 4h and 4j exhibited promising cytotoxicity against HeLa, MDA-MB-231 and MCF-7 cell lines compared to doxorubicin. a Results are expressed as IC50 values in lM concentrations.
In conclusion, we have synthesized a series of novel chromeno-annulated cis-fused pyrano[3,4-c]benzopyran and naphtho pyran derivatives and the cytotoxicity evaluation was performed against a panel of four cancer cell lines such as human lung adenocarcinoma epithelial cells, A549; human breast adenocarcinoma cell lines, MDA-MB-231 and MCF-7, and human cervical cancer cell line, HeLa, lines using an in vitro MTT assay. The results showed that compounds 4h and 4j exhibited promising cytotoxicity against HeLa, MDA-MB-231 and MCF-7 cell lines. While, the compound 4j showed most promising cytotoxicity against human lung cancer cell line A549, with IC50 value of 2.53 ± 0.07 lM, which was comparable to the standard doxorubicin (IC50 = 1.21 ± 0.1 lM). Based on these results, further synthetic studies on various novel chromeno-annulated cis-fused pyrano[3,4-c]benzopyran and naphtho pyran derivatives by altering the substituents on the chromenone nucleus and phenolic
or naphthol nucleus to enhance the anticancer activity are currently under investigation and will be reported in due course. Acknowledgments M. Jyothi thanks University Grant Commission (UGC), New Delhi for the award of fellowship and CSIR New Delhi for funding through the programme ORIGIN XII FYP (CSC0108). Supplementary data Supplementary data (general procedures, analytical data and cytotoxicity evaluation) associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.bmcl.2014.08.005.
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Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl
Synthesis of novel chromeno-annulated cis-fused pyrano[3,4-c]benzopyran and naphtho pyran derivatives via domino aldol-type/hetero Diels–Alder reaction and their cytotoxicity evaluation Jyothi Madda a, Akkaladevi Venkatesham a, Naveen Kumar Bejjanki a, Nagaiah Kommu a,⇑, Sujitha Pombala b, C. Ganesh Kumar b, Tadikamalla Prabhakar Rao c, Jagadeesh Babu Nanubolu d a
Division of Organic and Biomolecular Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India c Center for Nuclear Magnetic Resonance, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India d X-ray Crystallography Laboratory, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India b
a r t i c l e
i n f o
Article history: Received 28 March 2014 Revised 14 July 2014 Accepted 4 August 2014 Available online xxxx Keywords: Chromeno pyrano[3,4-c]benzopyran and naphtho pyrans Aldol-type/hetero Diels–Alder reaction cytotoxicity evaluation HeLa (cervical) MDA-MB-231 (breast) MCF-7 (breast) A549 (lung)
a b s t r a c t New chromeno-annulated cis-fused pyrano[3,4-c]benzopyran and naphtho pyran derivatives have been synthesized by domino aldol-type reaction/hetero Diels–Alder reaction generated from o-quinone methide in situ from 7-O-prenyl derivatives of 8-formyl-2,3-disubstituted chromenones with resorcinols/ naphthols in the presence of 20 mol % ethylenediamine diacetate (EDDA), triethylamine (2 mL) as co-catalyst in CH3CN under reflux conditions in good yields. The structures were established based on spectroscopic data, and further confirmed by X-ray diffraction analysis. The results showed that compounds 4h and 4j exhibited very potent cytotoxicity against human cervical cancer cell line (HeLa). Compound 4h displayed good inhibitory activity against both breast cancer cell lines, MDA-MB-231 and MCF-7. Further, the compound 4i exhibited good cytotoxicity against only MDA-MB-231, and compound 4j showed promising activity against human lung cancer cell line, A549 with IC50 value of 2.53 ± 0.07 lM, which was comparable to the standard doxorubicin (IC50 = 1.21 ± 0.1 lM). Ó 2014 Elsevier Ltd. All rights reserved.
Today, cancer posses one of the most serious health problems, that is difficult to treat due to the successive mutations on oncogenes and suppressor genes that deregulate the cell cycle.1 In recent years, combination of novel heterocyclic compounds and understanding the biology of cancer has been exceptionally improved anticancer activity2 by connecting with novel mechanisms, such as carcinogens inactivation, antiproliferation, cell cycle arrest, induction of apoptosis and differentiation, inhibition of angiogenesis, antioxidation and reversal of multidrug resistance.3 Now a days, many classes of drugs are being used for the treatment of cancer which have developed resistance in cancer therapy4 and unable to differentiate between normal and neoplastic cells or to overcome primary or secondary resistance mechanisms evolved in the cancer cells. Thus, there is a vital need for identifying new anticancer agents with high potency by preventing cancer cell proliferation, less toxicity in non-cancerous cells, and unique targets of ⇑ Corresponding author. E-mail address: [email protected] (K. Nagaiah).
action is still not precluded. In recent years, chromenopyrano/pyranopyrans containing heterocyclic synthesis has attracted tremendous interest among researchers due to their potential applications in medicinal chemistry (Fig. 1).5 2,2-Dimethylbenzopyran template, a structural motif found in numerous natural products, which have potential applications in medicine.6 This functionalized moiety exhibits diverse biological activities such as anticancer activity,7,8 anti-HIV activity,9 insecticidal,10 antifungal activity,11 potassium channel activators,12 aldosterone biosynthesis inhibitors,13 5-hydroxytryptamine-3 receptor antagonist,14 phosphodiesterase IV inhibitor,15 ampicillin-derived antibacterial agent,16 psychotropically active leukemia17 and solid tumor cell lines.18 On the other hand chromeno fused pyranopyran derivatives exhibit significant biological activities such as anti-tumour,19 anti-mycobacterial20 and antiviral activity.21,22 A single molecule containing more than one pharmacophore, each with different mode of action, is beneficial for the treatment of cancer.23,24 Implementation of these approaches in our research group, resulted in the design and synthesis of new hybrid molecules by
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coupling 2,3-disubstituted chromenopyrans and 2,2-dimethylbenzopyran or 2,2-dimethyl naphtho pyran with high stereo specificity. The present study is in continuation to our earlier efforts25 on the synthesis of biologically important compounds using the domino aldol-type/hetero Diels–Alder reaction and the importance of 2,2-dimethylbenzopyran or 2,2-dimethyl naphthopyran and chromenopyrano moieties. We prepared a new series of chromeno-annulated cis-fused pyrano[3,4-c]benzopyran and naphtho pyran derivatives in good yields and with excellent stereo selectivity and investigated their cytotoxicity against a panel of four different cancer cell lines, namely, MDA-MB-231, MCF-7, HeLa, and A549. Requisite 7-O-prenyl derivatives of 8-formyl-2,3-disubstituted chromenones were prepared from 2,3-disubstituted-7hydroxychromeno aldehydes in analogy to our previous work.25 Initially, the domino aldol-type/hetero Diels–Alder reaction, generated from o-quinone methide in situ from 7-O-prenyl derivatives of 8-formyl-2,3-dimethyl chromenones with resorcinol 2a or naphthol 2e in the presence of 20 mol % ethylenediamine diacetate (EDDA)26 and triethylamine (TEA; 2 mL) as co-catalyst in CH3CN at
O OMe MeO H
O O
O
O
O O
O H
O
O
O OH
deguelin
O
O
O O
morusin
HO
R O O
O R=H R = CH 2CH 3
OH O H
HO
O
OH
O
H O
OMe
O O
O
OMe OMe
OCH3
Lonchocarpusone
Calyxin J & Epicalyxin J
Figure 1. Chromeno fused pyrano/pyranopyran heterocyclic natural products.
O
O
H HO
R3
OH
H
O
O OH R1
R3
CHO O
O
R1 R2
+
O 2a: R3 = ethyl, 2b: R3 = methyl, 2c: R3 = benzyl, 2d: R3 = phenyl
R2 O 4a-j cis isomer only 80-90%
EDDA (20 mol%), TEA, CH3CN, 80-85 οC, 12 h
O H
O 1a: R1, R2 = CH 3 1 2 1b: R = H; R = CH 3 1c: R1 = CH 3; R2 = Ph
OH H
O
O
R1 R2
2e
O 4k-l cis isomer only 88-90%
Scheme 1.
Table 1 Optimization of the catalyst EDDA and solvent conditionsa on the reaction of 7-O-prenyl derivative of 8-formyl-2,3-dimethylchromen-4-one (1a) with resorcinol (2a) O CHO O
CH 3
H O
HO
CH3
OH
reagents and conditions
+ CH3 O 1a
H
O
CH3
O O OH CH 3
O
CH 3
2a
4a
O
Solvent
Catalyst (mol %)
Time (h)
Yieldb (%)
Xylene Xylene Xylene Toluene Toluene Toluene CH3CN CH3CN CH3CN CH2Cl2 CHCl3
5.0 10.0 20.0 5.0 10.0 20.0 5.0 10.0 20.0 20.0 20.0
12 12 12 12 12 12 12 12 12 12 12
50 63 70 20 28 42 50 64 78 12 20
Values in bold were measured under optimized best conditions. a Reagents and conditions: 1a (1.0 mmol), 2a (0.66 mmol), triethylamine (2 mL) and solvent (5 mL). b Isolated and unoptimized yields.
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J. Madda et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
O
CH3
HO CHO O
O
HO
CH 3 +
OH
O
O H 3C
O O CH3
O TEA
CH 3 1a
HO EDDA
CH3 2a
3
O
O
O CH 3
O
O
CH 3
OH O CH3
H 3C
CH3
H 3C
-H2O O
OH O
O
O End o-E-syn II
Exo-Z-syn I
O
O
H
H
CH3
CH3 H O
O
H
O O OH CH 3
O
O O OH CH 3 CH3
CH3 O 4a major trans isomer only
O 4a major cis isomer only
Scheme 2. Explanation of the observed stereochemistry.
O
O
O
HO
CH 3 +
OH
O
O
O
H 3C
CH3
EDDA, TEA -H 2O
CH3 1a
CH 3
O
CHO
2a
H 3C H3C
O
OO
O
O H
O OH H 3C
H3C
O End o-E-syn II Intra molecular hydrogen bonding
O End o-E-syn III No Hydrogen bondings
O
O
OH H
H
CH 3
CH 3 O
H O
O CH 3
CH 3 O 4a 1 major cis isomer only
O
H
O O OH CH 3
CH 3 O 4a major cis isomer only
Scheme 3. Explanation of the observed regiochemistry.
80–85 °C afforded the corresponding cis-fused pyrano[3,4-c]benzopyran/naphtho pyran derivatives 4a and 4k in 85% and 90% yields, respectively, with cis selectivity (Scheme 1). Furthermore, a systematic study was carried out for catalytic evaluation of EDDA for the reaction of 7-O-prenyl derivative of 8formyl-2,3-dimethylchromen-4-one 1a with resorcinol 2a under different solvent conditions with different catalytic loads. As shown in Table 1, different mol % of EDDA (5, 10 and 20) along with triethylamine as co-catalyst, were screened with various solvents like xylene, toluene, acetonitrile, dichloromethane and chloroform at reflux conditions, suggested that EDDA (20 mol %) provided a better yield. The effect of solvents was also examined, and CH3CN was identified as an optimal solvent.
The reaction proceeded via a domino aldol-type/hetero Diels– Alder reaction pathway. This reaction was highly stereoselective affording exclusively cis-fused pyrano[3,4-c]benzopyran and naphtho pyran derivatives (Scheme 2). These results could be explained nicely by assuming that the reactions were governed by stereo electronic and steric effects.27 Thus significantly, the stereo specificity of the formation of the major cis product 4a could be explained by a stereo electronic effect via an endo-E-syn-transition state (II) as shown in Scheme 2. At first instance, 7-O-prenyl-8-formyl-2, 3-dimethyl chromenone 1a reacted with resorcinol 2a in the presence of EDDA, triethylamine as co-catalyst to afford intermediate 3 as an aldol product, which underwent dehydration followed by intramolecular hetero
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(A)H C (B)H 3C3 O Hc Hd
O CH 3
Hb O
Ha
O OH CH 3 O
4e
Figure 2. Characteristic NOE and energy-minimized structure of 4e.
Diels–Alder reaction. The o-quinone methide may potentially follow two pathways for the hetero-Diels–Alder reaction in which the endo-E-syn-transition state (II) might have been more favorable than the exo-Z-syn transition state (I) due to an sp2-geminal effect, according to the phenomenon of 1,3-allylic strain, which had been already proved by Tietze’s work,28 to afford the cisadduct 4a exclusively. In addition, the regiospecificity of the major product 4a formation over 4a1 could be explained as shown in Scheme 3. Accordingly, the interaction of the resorcinol 2a with 7-O-prenyl derivatives of 8-formyl-2,3-dimethyl chromenones 1a by aldol reaction followed by dehydration to form two possible o-quinone methide intermediates 4a and 4a1 in endo-E-syn fashion. The o-quinone methide adduct 4a was favourable heterodiene than 4a1. This selectivity could be explained by the deactivation of the o-OH group by an intramolecular hydrogen bonding29 with the neighbouring carbonyl group, as confirmed by 1H NMR analysis of 4a, in which a singlet peak corresponding to the o-OH proton was observed at d 13.1 ppm. The stereo- and regio-selectivity of the investigated hetero Diels– Alder reactions carried out in this work were similar to those of earlier reported intermolecular analogues.30 The stereochemistry of the product 4e was assigned on the basis of 1H NMR J-coupling constants and NOE studies. In the 1H NMR spectrum, the vicinal coupling constant JHa–Hb = 5.2 Hz in between Ha (d 4.71 ppm) and Hb (d 2.21 ppm) indicated an equatorial and axial orientation of these protons, respectively, in a chair conformation, which confirmed that the two six membered tetra hydropyran rings were cis-fused. In addition, the observed vicinal coupling constants like JHb–Hc = 5.2 Hz, JHb–Hd = 11.3 Hz and x coupling of JHa–Hc = 1.5 Hz, confirmed the positions of Ha, Hb, Hc, and Hd as shown in Figure 2. The presence of NOE correlations between Ha/Hb, Hb/Hc, Ha/Me-A and Hb/Me-A and Me-B further supported the above observation. The energy-minimized structure of 4e was in full agreement with the above NMR analysis (Fig. 2). Further, the stereochemistry was also assigned by COSY and HSQC studies. Moreover, the spatial stereochemistry of the product 4a was also confirmed by single crystal X-ray diffraction (CCDC deposition
number 905891). It represented that the asymmetric unit was consisting of two molecules with a single molecular structure (Fig. 3). To investigate the scope of EDDA-catalyzed synthesis of chromenoannulated cis-fused pyrano[3,4-c]benzopyran and naphtho pyran derivatives, several o-quinone methides (derived in situ from resorcinols or naphthols and 7-O-prenyl derivatives of 8-formyl2,3-disubstituted chromenones in CH3CN) were examined under similar reaction conditions and the results were summarized in Table 2. Thus, we synthesized a novel series of chromeno-annulated cisfused pyrano[3,4-c]benzopyran and naphtho pyran derivatives (4a–l) in good to excellent yields and all the products were new and characterized by 1H NMR, 13C NMR, IR and mass spectroscopic techniques. The inhibitory efficiency (IC50 values) was tested for all the synthesized chromeno-annulated cis-fused pyrano[3,4-c]benzopyran and naphtho pyran derivatives against a panel of four different cancer cell lines such as MDA-MB-231, MCF-7, A549 and HeLa. The MTT assay was performed by following the previously reported protocol in a 96 well plate.31 Results of the in vitro anticancer activity were compared with the reference drug, Doxorubicin. Further, the active compounds 4h–j did not exhibit any cytotoxicity on HEK293 cell line derived from human normal embryonic kidney cells. Table 3 showed the IC50 values of chromeno-annulated cis-fused pyrano[3,4-c]benzopyran and naphtho pyran derivatives against different cancer cell lines and some of them displayed improved activity as compared to the standard Doxorubicin. Specially, the compound 4h exhibited promising cytotoxicity against different cell lines such as HeLa, MDA-MB-231 and MCF-7 and further it was 3fold less potent (IC50 = 1.5 ± 0.08 lM) than Doxorubicin (IC50 = 0.45 ± 0.07 lM), while 4i and 4j showed good cytotoxicity selectively against MDA-MB-231 and HeLa, respectively. Further, compound 4j also displayed selective cytotoxicity and was 2-fold less potent (IC50 = 2.53 ± 0.07 lM) than doxorubicin (IC50 = 1.21 ± 0.1 lM), against A549 cell line. Our efforts to understand the structure-activity relationship of the lead compound 4h showed broad cytotoxicity against HeLa, MDA-MB-231 and MCF-7 cell lines, which suggested the presence of phenyl substitution on the carbonyl group and also the presence of mono methyl substituent on the chromenone moiety. In addition, in case of compounds 4i and 4j the basis of cytotoxicity was due to the presence of ethyl and methyl substituents on the carbonyl group, respectively, and also the existence of phenyl and methyl substituents on the chromenone moiety. In general, it was observed that the compounds with 3-methyl, 2-phenyl, and only 2-methyl substitutions on the chromenone moiety seems to exhibit promising cytotoxicity as compared to the presence of 2, 3-dimethyls on the chromenone moiety.
Figure 3. ORTEP diagram for the compound 4a, with displacement ellipsoids drawn at 30% probability level.
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J. Madda et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx Table 2 EDDA catalyzed synthesis of chromeno-annulated cis-fused pyrano[3,4-c]benzopyran and naphtho pyran derivativesa Entry
Aldehyde type
Productb (4a–l)
Resorcinol type HO
CHO O
O
OH
O
CH3 CH3
O
Yieldc (%)
12
85
12
86
12
88
12
90
12
80
12
81
12
82
12
88
12
83
O
H
CH 3
CH 3
a
Time (h)
H
O
O OH CH3
O CH3 O HO
CHO O
O
b
OH
CH3
O
O
CH3
O
H
CH 3
CH3 H
O
O OH CH
3
O CH3 O HO
CHO O
O
OH
O
CH 3
O
H
Ph
Ph CH 3
c
O
H
O
O OH CH3
O CH3 O CHO
HO
O
O
d
OH
CH 3
O
CH 3
O
H
Ph
Ph H
O
O
O OH CH3
O CH3 O CHO
HO
O
OH
O
O
CH3
CH 3
e
O
H O
CH3
H
O
O OH
O CH3 O CHO
HO
O
OH
O
f
O CH3
CH3
CH 3 H
O
O
O
H O OH
O CH3 O CHO
HO
O
OH
O
O
Ph
Ph
g
O
H CH3
H
O
O
O OH
O CH3 O
CHO O
HO
OH
O
h
O
O
CH3
O
H
Ph
Ph H
O
O OH
O CH 3 O CHO O
HO O
OH
O
CH3 CH3 Ph
i
O
H O
O
CH3 H
O OH CH 3
O Ph O
(continued on next page)
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J. Madda et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
Table 2 (continued) Entry
Aldehyde type
Productb (4a–l)
Resorcinol type HO
CHO O
O
OH
CH 3 O
Ph
j
O
Yieldc (%)
12
83
12
90
12
88
O
H
CH 3
Time (h)
CH3 H
O
O OH CH 3
O Ph O CHO O
OH O
CH 3
O H
CH 3
k
O
H
O
O
CH 3 CH 3
O CHO O
OH O
O CH 3
l
O
O
H
O CH 3 O
a b c
Reagents and conditions: aldehyde 1 (1.0 mmol), resorcinol or naphthol 2 (0.66 mmol), EDDA (20 mol %), triethylamine (2 mL) and solvent (5 ml), 80–85 °C. All product were characterized by 1H, 13C NMR, IR and mass spectroscopic techniques. Isolated yields.
Table 3 Cytotoxicity evaluation of compounds 4a–la Compound (lg mL
4a 4b 4c 4d 4e 4f‘ 4g 4h 4i 4j 4k 4l Doxorubicin
1
IC50 values (in lM)
) HeLa
MDA-MB-231
MCF-7
A549
>100 >100 >100 >100 >100 >100 >100 1.5 ± 0.08 18.19 ± 0.25 4.81 ± 0.13 >100 >100 0.45 ± 0.07
>100 >100 >100 >100 >100 >100 >100 5.68 ± 0.13 6.15 ± 0.09 46.8 ± 0.59 >100 >100 0.50 ± 0.06
>100 >100 >100 >100 >100 >100 >100 6.24 ± 0.19 20.5 ± 0.65 11.23 ±0.27 >100 >100 1.05 ± 0.09
>100 >100 >100 >100 >100 >100 >100 16.98 ± 0.27 19.26 ± 0.98 2.53 ± 0.07 >100 >100 1.21 ± 0.1
Values in bold indicate that 4h and 4j exhibited promising cytotoxicity against HeLa, MDA-MB-231 and MCF-7 cell lines compared to doxorubicin. a Results are expressed as IC50 values in lM concentrations.
In conclusion, we have synthesized a series of novel chromeno-annulated cis-fused pyrano[3,4-c]benzopyran and naphtho pyran derivatives and the cytotoxicity evaluation was performed against a panel of four cancer cell lines such as human lung adenocarcinoma epithelial cells, A549; human breast adenocarcinoma cell lines, MDA-MB-231 and MCF-7, and human cervical cancer cell line, HeLa, lines using an in vitro MTT assay. The results showed that compounds 4h and 4j exhibited promising cytotoxicity against HeLa, MDA-MB-231 and MCF-7 cell lines. While, the compound 4j showed most promising cytotoxicity against human lung cancer cell line A549, with IC50 value of 2.53 ± 0.07 lM, which was comparable to the standard doxorubicin (IC50 = 1.21 ± 0.1 lM). Based on these results, further synthetic studies on various novel chromeno-annulated cis-fused pyrano[3,4-c]benzopyran and naphtho pyran derivatives by altering the substituents on the chromenone nucleus and phenolic
or naphthol nucleus to enhance the anticancer activity are currently under investigation and will be reported in due course. Acknowledgments M. Jyothi thanks University Grant Commission (UGC), New Delhi for the award of fellowship and CSIR New Delhi for funding through the programme ORIGIN XII FYP (CSC0108). Supplementary data Supplementary data (general procedures, analytical data and cytotoxicity evaluation) associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.bmcl.2014.08.005.
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J. Madda et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
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