- Email: [email protected]
Combinatorial Chemistry Online
Combinatorial Chemistry - An Online Journal 7 (2005) 33–36
Combinatorial Chemistry Online Volume 7, Issue 8, August 2005 N. K. Terrett Pfizer Global R&D, Cambridge, MA 02139 USA
1. Current literature highlights
OH
1.1. Peptide-Cationic Steroid Antibiotic Conjugates
O O
Cationic steroid antibiotics were developed to mimic the antibacterial behaviour of endogenous peptide antibiotics, including selective association with, and disruption of, bacterial membranes. This association/disruption behaviour results in rapid decline in bacterial activity with a minimal potential for causing the emergence of resistance. Many of these antibiotics adopt cationic, facially amphiphilic conformations (such as (i)), and these appear to be the key requirement for antibacterial activity. Membrane selectivity is derived primarily from ionic recognition of negatively charged bacterial membranes. Bacterial membrane components however present more than anionic groups, so it could be expected that additional associative non-covalent interactions would increase affinity of membrane-active antibiotics for bacterial membranes and thereby increase antibacterial activity. Consequently, recent work has been directed toward building the functionality presented by cationic steroid antibiotics.1 Cationic steroid antibiotics are relatively rigid structures displaying a great deal of preorganisation, so any functionality intended to interact with bacterial membrane components needs to be on the polar face. In this paper, a library of 216 peptide cationic steroid antibiotic conjugates were prepared with general structure (ii). Following preparation of this library, compounds were screened for activity against Gram-negative (Escherichia coli (ATCC 25922)) and Gram-positive (Staphylococcus aureus (ATCC 25923)) bacteria using a micro-broth dilution method. Sequences of tripeptides yielding cationic steroid antibiotic-peptide conjugates with good
E-mail: nick.terrett@pfizer.com doi:10.1016/j.comche.2005.07.001
O
(i) H2N NH2
H2N
OH NH NH AA1 NH
AA1 AA2
AA1
AA2 AA3
AA2
AA3 NH2
AA3
NH2
(ii)
NH2 OH NH NH R NH
R
R
NH2
NH2
NH2
(iii)
R = FFK (Phe-Phe-Lys)
antibacterial properties were found. One of the most potent compounds discovered was (iii) which possessed an MIC of 8 lg/mL against S. aureus and E. coli. This work rapidly identified key requirements for peptidecontaining cationic steroid antibiotics and discovered compounds that appear to offer an improvement in antibacterial activity. 1.2. Stabilisation of Oligonucleotide Complexes Selective molecular recognition between synthetic oligonucleotide ligands and nucleic acid targets plays an
34
N. K. Terrett / Combinatorial Chemistry - An Online Journal 7 (2005) 33–36
important role in molecular biology and biotechnology. Natural DNA or RNA oligonucleotides, either identified via in vitro selection or through rational design, will often generate lead compounds. The improvement of their properties, such as affinity, nuclease resistance and membrane permeability, often requires the introduction of chemical modifications, and these modifications can prove difficult, especially for binders to structured RNA targets. Recent work has been directed towards the identification of covalently appended small molecules that stabilise nucleic acid complexes through the use of dynamic combinatorial chemistry.2 The emerging field of dynamic combinatorial chemistry involves the use of reversible reactions to generate an equilibrating mixture of molecules within the dynamic combinatorial library (DCL). The composition of this DCL is able to respond to molecular-recognition events resulting when the library is in the presence of a target of interest. The preferential binding of one member of the DCL to the target induces a shift in the equilibrium towards the formation of that particular compound. Whereas traditional combinatorial chemistry library synthesis and screening are two separate and sequential pro-
cesses, dynamic combinatorial chemistry offers in situ screening of the combinatorial library by comparing its composition in the presence and absence of the target. The present work uses this concept with an oligonucleotide ligand bearing a reactive amino group (iv) which is reacted reversibly with a set of aldehydes (v) in aqueous media. The resulting mixture of imines (vi) at equilibrium is responsive to its environment. The addition of a nucleic acid target that develops interactions with imine products should promote the preferential formation of the strongest binders. Subsequently, the mixture of interconverting imine species is reduced with sodium cyanoborohydride to form chemically stable amines (vii), facilitating isolation and analysis of the final mixture. This concept was used to provide for the first successful use of dynamic combinatorial chemistry for the rapid identification of a non-nucleic acid residue appended to an oligonucleotide ligand that stabilises the complex formed with its nucleic acid target. This was achieved with both a DNA duplex and with a tertiary-structured RNA-RNA complex, and further work is being undertaken to expand the set of aldehydes and 2 0 -amino-2 0 deoxynucleotides present amongst the ligands used. 2. A summary of the papers in this month’s issue 2.1. Solid-phase synthesis
O
A bimetallic titanium(salen) complex has been used to catalyse the asymmetric addition of potassium cyanide to aldehydes attached to Wang resin giving polymer supported cyanohydrin propionates with up to 91% enantiomeric excesses.3
NH HO N
O
O
OO P O
NH2
O
(iv)
The solid-phase synthesis of quinoxaline derivatives has been accomplished through successive introduction of building blocks such as amines, methoxide, acid chlorides, and isocyanates into 6-amino-2,3-dichloroquinoxaline loaded on AMEBA resin.4
NH2 U A
5´
G C
An efficient and robust solid-phase synthesis of 6-substituted-2,5,6,8-tetrahydro-3H-imidazo[1,2-a]pyrimidin-7ones, 3-substituted-1,3,4,6,7,8-hexahydro-pyrimido[1,2-a]pyrimidin-2-ones and 3-substituted-3,4,6,7,8,9-hexahydro-1H-pyrimido[1,2-a][1,3]diazepin-2-ones has been developed, and validated through an automated parallel synthesis of a small library of fourteen compounds of the 3H-imidazo[1,2-a]pyrimidin-7-one series.5
41
C G
+
33
G C
RCHO (v)
43
C G 37
A U
3` NH2
R
N
HN
U A
U A
G C
G C
82
NaBH3CN
C G 65
G C
78
113
C G
C G
69
104
A U
A U N
R
NH
(vii) R
A traceless solid-phase synthetic route to 1,4-disubstituted-6-nitro-3,4-dihydro-1H-quinazolin-2-ones in high yield and purity has been described.6 An effective solid-phase preparation of anilides from supported carboxylic acids has been described using a route that requires their activation as the corresponding acid chlorides with N-[chloro(dimethylamino)methylene]-N-methylmethanaminium chloride (TMUCl Cl).7
117
C G
100
G C (vi)
R
The solid-phase synthesis of a 17-mer cyclopeptide which is expected to have anti-angiogenic properties has been
N. K. Terrett / Combinatorial Chemistry - An Online Journal 7 (2005) 33–36
reported. Synthesis was performed on an allyldimethylsilyl polystyrene support loaded by metathesis with a conveniently functionalised D -tyrosine amino acid.8 2.2. Solution-phase synthesis A liquid-phase synthetic route to a library of 3-alkylamino-4,5-disubstituted-1,2,4-triazoles has been developed, which permits the incorporation of three elements of diversity. The heterocycle was constructed upon PEG6000 (soluble polymer) modified by 4-hydroxy-2-methoxybenzaldehyde, from which a traceless cleavage could be achieved with TFA/CH2Cl2.9
35
accessible non-steroidal mimetics suitable for parallel synthesis have been investigated.16 A library of boron-containing carbonic anhydrase (CA, EC 4.2.1.1) inhibitors, including sulphonamides, sulphamides, and sulphamates has been reported and assayed for the inhibition of three physiologically relevant CA isozymes.17 Following the discovery that 2,6-dichloro-N-[2-(cyclopropanecarbonylamino)benzothiazol-6-yl] benzamide exhibited excellent in vivo inhibitory effect on tumour growth, a compound library was synthesised for structure optimisation.18
2.3. Scaffolds for combinatorial libraries The construction on SASRIN (super acid sensitive resin) of an L -proline scaffold that enforces a defined beta-turn loop for RGD has been reported.10
Sets of isomeric thiazole derivatives have been synthesised in a parallel iterative solution-phase synthesis approach guided by biological results and computeraided design and analysis, leading to highly active isomeric NPY5 receptor ligands.19
A reliable and efficient way for the synthesis of N9-alkylated purine library scaffolds, using tetrabutylammonium fluoride (TBAF) to accelerate the N9-alkylation of purine derivatives, has been reported. These mild reaction conditions permitted the use in combinatorial reactions in microtiter plates followed by in situ screening for the discovery of potent sulphotransferase inhibitors.11
Novel 3-thio-1,2,4-triazoles have been obtained via a solution-phase parallel synthesis strategy, affording potent non-peptidic agonists for the human somatostatin receptor subtypes 2 and 5.20
2.4. Solid-phase supported reagents Osmium tetroxide has been immobilised onto a shortlength PEGylated ionic polymer, which exhibited excellent catalytic performance in OsO4-catalysed asymmetric dihydroxylation.12 A range of alkyl spacer-tethered 1,2- and 1,3-diols have been prepared from commercially available Merrifield resin and (4-chloromethyl)phenylpentyl-polystyreneco-divinylbenzene. The utility of these resin-bound diols as supports for the Ti(IV)-catalysed Diels–Alder reaction has been described.13 The initial synthesis of UK-427,857 (Maraviroc), a potent antagonist of the CCR5 receptor, has been described including the preparation of 4,4-difluorocyclohexanoic acid and amide coupling utilising a polymer supported reagent.14 Polymer-supported chiral phosphinooxazolidine (POZ) ligands and cationic palladium-POZ catalysts have been prepared. The former ligands were used in the Pd-catalysed asymmetric allylic alkylation, while the latter catalysts were used in Diels–Alder chemistry.15 2.5. Novel resins, linkers and techniques No papers this month. 2.6. Library applications Non-steroidal mimetics of mifepristone and progesterone are important templates for modulation of the progesterone receptor and thus unexplored, synthetically
In a three-step sequence, an array of angularly fused polycyclic heterocycles with coumarin, benzofuran and pyridine rings were synthesised, fully characterised and screened for anti-microbial, anti-inflammatory and analgesic activities.21 Novel inhibitors of human dipeptidyl peptidase I (hDPPI, cathepsin C, EC 3.4.14.1) have been discovered via screening of a one-bead-two-compounds library of semicarbazide derivatives.22 A library of polyamine–peptide conjugates based around some previously identified inhibitors of trypanothione reductase have been synthesised by parallel solidphase chemistry and screened.23 Nucleoside bases have been constructed on Merrifield resin by sequential displacement of purine dichloride with amines, and after detachment, the purine analogues were condensed with D ,L -ribofuranoside compounds by the Vorbru¨ggen method and tested for activity against HIV-1 in PBM cells.24 A chemical library of substituted dihydropteridinones has been screened to identify a non-toxic, cell permeable, and reversible inhibitor of the RNAi pathway in human cells.25 References 1. Ding, B. et al. Organic Letters 2004, 6 (20), 3433–3436. 2. Bugaut, A. et al. Angew. Chem., Int. Ed. 2004, 43 (24), 3144–3147. 3. Belokon, Y. N. et al. Tetrahedron Lett. 2005, 46 (26), 4483–4486. 4. Jeon, M.-K. et al. Tetrahedron Lett. 2005, 46 (30), 4979–4983.
36
N. K. Terrett / Combinatorial Chemistry - An Online Journal 7 (2005) 33–36
5. Pathak, R. et al.. Tetrahedron Lett. 2005, 46 (32), 5289–5292. 6. Wang, X. et al. Tetrahedron Lett. 2005, 46 (32), 5361–5364. 7. Vendrell, M. et al. Tetrahedron Lett. 2005, 46 (32), 5383–5386. 8. Gonc¸alves, M. et al. Tetrahedron 2005, 61 (32), 7789–7795. 9. Zong, Y.-X. et al. Tetrahedron Lett. 2005, 46 (31), 5139–5141. 10. Enholm, E.; Bharadwaj, A. Bioorg. Med. Chem. Lett. 2005, 15 (14), 3470–3471. 11. Brik, A. et al. Bioorg. Med. Chem. 2005, 13 (15), 4622–4626. 12. Lee, B. S. et al. Tetrahedron Lett. 2005, 46 (26), 4491–4493. 13. Dyer, P. W. et al. Tetrahedron Lett. 2005, 46 (28), 4753–4756. 14. Price, D. A. et al. Tetrahedron Lett. 2005, 46 (30), 5005–5007. 15. Nakano, H. et al. Tetrahedron: Asymmetry 2005, 16 (12), 2133–2140. 16. Jones, D. G. et al. Bioorg. Med. Chem. Lett. 2005, 15 (13), 3203–3206. 17. Winum, J.-Y. et al. Bioorg. Med. Chem. Lett. 2005, 15 (13), 3302–3306. 18. Yoshida, M. et al. Bioorg. Med. Chem. Lett. 2005, 15 (14), 3328–3332. 19. Nettekoven, M. et al. Bioorg. Med. Chem. Lett. 2005, 15 (14), 3446–3449. 20. Contour-Galce´ra, M.-O. et al. Bioorg. Med. Chem. Lett. 2005, 15 (15), 3555–3559. 21. Khan, I. A. et al. Bioorg. Med. Chem. Lett. 2005, 15 (15), 3584–3587. 22. Bondebjerg, J. et al. Bioorg. Med. Chem. 2005, 13 (14), 4408–4424. 23. Dixon, M. J. et al. Bioorg. Med. Chem. 2005, 13 (14), 4513–4526. 24. Chang, J. et al. Bioorg. Med. Chem. 2005, 13 (15), 4760–4766. 25. Chiu, Y.-L. et al. Chem. Biol. 2004, 12 (6), 643–648.
Further reading Papers on combinatorial chemistry or solid-phase synthesis from other journals Nold, M.; Koch, K.; Wennemers, H. Acid-rich peptides are prone to damage under fenton conditions - split-and-mix libraries for the detection of selective peptide cleavage. Synthesis 2005 (9), 1455–1458. Lovrinovic, M.; Niemeyer, C. M. DNA microarrays as decoding tools in combinatorial chemistry and chemical biology. Angewandte Chemie, International Edition 2005, 44 (21), 3179–3183. Kumar, A.; Koul, S.; Razdan, T. K.; Andotra, C. S. A single pot synthesis of new dimeric 2-phenyl-10,3a-dihydro-1,3,4oxadiazolino[3,2-a]quinazolin-6-ols. Journal of Heterocyclic Chemistry 2005, 42 (4), 487–491. Corbett, P. T.; Sanders, J. K. M.; Otto, S. Competition between receptors in dynamic combinatorial libraries: amplification of the fittest? Journal of the American Chemical Society 2005, 127 (26), 9390–9392. Corbett, P. T.; Tong, L. H.; Sanders, J. K. M.; Otto, S. Diastereoselective amplification of an induced-fit receptor from a dynamic combinatorial library. Journal of the American Chemical Society 2005, 127 (25), 8902–8903.
Patek, M.; Weichsel, A. S.; Drake, B.; Smrcina, M. Solidphase synthesis of disubstituted 1,3-dihydro-2H-imidazol2-ones. Synlett 2005 (8), 1322–1324. Nielsen, T. E.; Meldal, M. Highly efficient solid-phase oxidative cleavage of olefins by OsO4-NaIO4 in the intramolecular N-acyliminium Pictet-Spengler reaction. Organic Letters 2005, 7 (13), 2695–2698. Tajbakhsh, M.; Hosseinzadeh, R.; Sadatshahabi, M. Synthesis and application of 2,6-dicarboxy pyridinium fluorochromate as a new solid-phase oxidant. Synthetic Communications 2005, 35 (11), 1547–1554. Sagara, Y.; Mitsuya, M.; Uchiyama, M.; Ogino, Y.; Kimura, T.; Ohtake, N.; Mase, T. Discovery of 2-aminothiazole-4carboxamides, a novel class of muscarinic M3 selective antagonists, through solution-phase parallel synthesis. Chemical & Pharmaceutical Bulletin 2005, 53 (4), 437–440. West, K. R.; Bake, K. D.; Otto, S. Dynamic combinatorial libraries of disulfide cages in water. Organic Letters 2005, 7 (13), 2615–2618. Dothager, R. S.; Putt, K. S.; Allen, B. J.; Leslie, B. J.; Nesterenko, V.; Hergenrother, P. J. Synthesis and identification of small molecules that potently induce apoptosis in melanoma cells through G1 cell cycle arrest. Journal of the American Chemical Society 2005, 127 (24), 8686–8696. Gendre, F.; Yang, M.; Diaz, P. Solid-phase synthesis of diaryl sulfides: direct coupling of solid-supported aryl halides with thiols using an insoluble polymer-supported reagent. Organic Letters 2005, 7 (13), 2719–2722. Guo, H.; Wang, Z.; Ding, K. PEG-polymer-supported liquidphase combinatorial synthesis of structurally diverse 2,3dihydro-4-pyridones. Synthesis 2005 (7), 1061–1068. Ohno, H.; Tanaka, H.; Takahashi, T. Solid-supported sulfonylhydroxylamine as an effective N-aminating agent of anilines. Synlett 2005 (7), 1191–1194. Houghten, R. A.; Yu, Y. ‘‘Volatilizable’’ supports for highthroughput organic synthesis. Journal of the American Chemical Society 2005, 127 (24), 8582–8583. Jian, H.; Tour, J. M. Preparative fluorous mixture synthesis of diazonium-functionalized oligo(phenylene vinylene)s. Journal of Organic Chemistry 2005, 70 (9), 3396–3424. Gachkova, N.; Cassel, J.; Leue, S.; Kann, N. The solid-phase Nicholas reaction: scope and limitations. Journal of Combinatorial Chemistry 2005, 7 (3), 449–457. Fuchi, N.; Doi, T.; Takahashi, T. A library synthesis of pyrazoles by azomethine imine cycloaddition to the polymer-supported vinylsulfone. Chemistry Letters 2005, 34 (3), 438–439. Krattiger, P.; Wennemers, H. Water-soluble diketopiperazine receptors - selective recognition of arginine-rich peptides. Synlett 2005 (4), 706–708. Martinez-Teipel, B.; Teixido, J.; Pascual, R.; Mora, M.; Pujola, J.; Fujimoto, T.; Borrell, J. I.; Michelotti, E. L. 2Methoxy-6-oxo-1,4,5,6-tetrahydropyridine-3-carbonitriles: versatile starting materials for the synthesis of libraries with diverse heterocyclic scaffolds. Journal of Combinatorial Chemistry 2005, 7 (3), 436–448. Ying, L.; Liu, R.; Zhang, J.; Lam, K.; Lebrilla, C. B.; GervayHague, J. A topologically segregated one-bead-one-compound combinatorial glycopeptide library for identification of lectin ligands. Journal of Combinatorial Chemistry 2005, 7 (3), 372–384. Fancelli, D.; Berta, D.; Bindi, S.; Cameron, A.; Cappella, P.; Carpinelli, P.; Catana, C.; Forte, B.; Giordano, P.; Giorgini, M. L.; Mantegani, S.; Marsiglio, A.; Meroni, M.; Moll, J.; Pittala, V.; Roletto, F.; Severino, D.; Soncini, C.; Storici, P.; Tonani, R.; Varasi, M.; Vulpetti, A.; Vianello, P. Potent and selective Aurora inhibitors identified by the expansion of a novel scaffold for protein kinase inhibition. Journal of Medicinal Chemistry 2005, 48 (8), 3080–3084.
Combinatorial Chemistry Online Volume 7, Issue 8, August 2005 N. K. Terrett Pfizer Global R&D, Cambridge, MA 02139 USA
1. Current literature highlights
OH
1.1. Peptide-Cationic Steroid Antibiotic Conjugates
O O
Cationic steroid antibiotics were developed to mimic the antibacterial behaviour of endogenous peptide antibiotics, including selective association with, and disruption of, bacterial membranes. This association/disruption behaviour results in rapid decline in bacterial activity with a minimal potential for causing the emergence of resistance. Many of these antibiotics adopt cationic, facially amphiphilic conformations (such as (i)), and these appear to be the key requirement for antibacterial activity. Membrane selectivity is derived primarily from ionic recognition of negatively charged bacterial membranes. Bacterial membrane components however present more than anionic groups, so it could be expected that additional associative non-covalent interactions would increase affinity of membrane-active antibiotics for bacterial membranes and thereby increase antibacterial activity. Consequently, recent work has been directed toward building the functionality presented by cationic steroid antibiotics.1 Cationic steroid antibiotics are relatively rigid structures displaying a great deal of preorganisation, so any functionality intended to interact with bacterial membrane components needs to be on the polar face. In this paper, a library of 216 peptide cationic steroid antibiotic conjugates were prepared with general structure (ii). Following preparation of this library, compounds were screened for activity against Gram-negative (Escherichia coli (ATCC 25922)) and Gram-positive (Staphylococcus aureus (ATCC 25923)) bacteria using a micro-broth dilution method. Sequences of tripeptides yielding cationic steroid antibiotic-peptide conjugates with good
E-mail: nick.terrett@pfizer.com doi:10.1016/j.comche.2005.07.001
O
(i) H2N NH2
H2N
OH NH NH AA1 NH
AA1 AA2
AA1
AA2 AA3
AA2
AA3 NH2
AA3
NH2
(ii)
NH2 OH NH NH R NH
R
R
NH2
NH2
NH2
(iii)
R = FFK (Phe-Phe-Lys)
antibacterial properties were found. One of the most potent compounds discovered was (iii) which possessed an MIC of 8 lg/mL against S. aureus and E. coli. This work rapidly identified key requirements for peptidecontaining cationic steroid antibiotics and discovered compounds that appear to offer an improvement in antibacterial activity. 1.2. Stabilisation of Oligonucleotide Complexes Selective molecular recognition between synthetic oligonucleotide ligands and nucleic acid targets plays an
34
N. K. Terrett / Combinatorial Chemistry - An Online Journal 7 (2005) 33–36
important role in molecular biology and biotechnology. Natural DNA or RNA oligonucleotides, either identified via in vitro selection or through rational design, will often generate lead compounds. The improvement of their properties, such as affinity, nuclease resistance and membrane permeability, often requires the introduction of chemical modifications, and these modifications can prove difficult, especially for binders to structured RNA targets. Recent work has been directed towards the identification of covalently appended small molecules that stabilise nucleic acid complexes through the use of dynamic combinatorial chemistry.2 The emerging field of dynamic combinatorial chemistry involves the use of reversible reactions to generate an equilibrating mixture of molecules within the dynamic combinatorial library (DCL). The composition of this DCL is able to respond to molecular-recognition events resulting when the library is in the presence of a target of interest. The preferential binding of one member of the DCL to the target induces a shift in the equilibrium towards the formation of that particular compound. Whereas traditional combinatorial chemistry library synthesis and screening are two separate and sequential pro-
cesses, dynamic combinatorial chemistry offers in situ screening of the combinatorial library by comparing its composition in the presence and absence of the target. The present work uses this concept with an oligonucleotide ligand bearing a reactive amino group (iv) which is reacted reversibly with a set of aldehydes (v) in aqueous media. The resulting mixture of imines (vi) at equilibrium is responsive to its environment. The addition of a nucleic acid target that develops interactions with imine products should promote the preferential formation of the strongest binders. Subsequently, the mixture of interconverting imine species is reduced with sodium cyanoborohydride to form chemically stable amines (vii), facilitating isolation and analysis of the final mixture. This concept was used to provide for the first successful use of dynamic combinatorial chemistry for the rapid identification of a non-nucleic acid residue appended to an oligonucleotide ligand that stabilises the complex formed with its nucleic acid target. This was achieved with both a DNA duplex and with a tertiary-structured RNA-RNA complex, and further work is being undertaken to expand the set of aldehydes and 2 0 -amino-2 0 deoxynucleotides present amongst the ligands used. 2. A summary of the papers in this month’s issue 2.1. Solid-phase synthesis
O
A bimetallic titanium(salen) complex has been used to catalyse the asymmetric addition of potassium cyanide to aldehydes attached to Wang resin giving polymer supported cyanohydrin propionates with up to 91% enantiomeric excesses.3
NH HO N
O
O
OO P O
NH2
O
(iv)
The solid-phase synthesis of quinoxaline derivatives has been accomplished through successive introduction of building blocks such as amines, methoxide, acid chlorides, and isocyanates into 6-amino-2,3-dichloroquinoxaline loaded on AMEBA resin.4
NH2 U A
5´
G C
An efficient and robust solid-phase synthesis of 6-substituted-2,5,6,8-tetrahydro-3H-imidazo[1,2-a]pyrimidin-7ones, 3-substituted-1,3,4,6,7,8-hexahydro-pyrimido[1,2-a]pyrimidin-2-ones and 3-substituted-3,4,6,7,8,9-hexahydro-1H-pyrimido[1,2-a][1,3]diazepin-2-ones has been developed, and validated through an automated parallel synthesis of a small library of fourteen compounds of the 3H-imidazo[1,2-a]pyrimidin-7-one series.5
41
C G
+
33
G C
RCHO (v)
43
C G 37
A U
3` NH2
R
N
HN
U A
U A
G C
G C
82
NaBH3CN
C G 65
G C
78
113
C G
C G
69
104
A U
A U N
R
NH
(vii) R
A traceless solid-phase synthetic route to 1,4-disubstituted-6-nitro-3,4-dihydro-1H-quinazolin-2-ones in high yield and purity has been described.6 An effective solid-phase preparation of anilides from supported carboxylic acids has been described using a route that requires their activation as the corresponding acid chlorides with N-[chloro(dimethylamino)methylene]-N-methylmethanaminium chloride (TMUCl Cl).7
117
C G
100
G C (vi)
R
The solid-phase synthesis of a 17-mer cyclopeptide which is expected to have anti-angiogenic properties has been
N. K. Terrett / Combinatorial Chemistry - An Online Journal 7 (2005) 33–36
reported. Synthesis was performed on an allyldimethylsilyl polystyrene support loaded by metathesis with a conveniently functionalised D -tyrosine amino acid.8 2.2. Solution-phase synthesis A liquid-phase synthetic route to a library of 3-alkylamino-4,5-disubstituted-1,2,4-triazoles has been developed, which permits the incorporation of three elements of diversity. The heterocycle was constructed upon PEG6000 (soluble polymer) modified by 4-hydroxy-2-methoxybenzaldehyde, from which a traceless cleavage could be achieved with TFA/CH2Cl2.9
35
accessible non-steroidal mimetics suitable for parallel synthesis have been investigated.16 A library of boron-containing carbonic anhydrase (CA, EC 4.2.1.1) inhibitors, including sulphonamides, sulphamides, and sulphamates has been reported and assayed for the inhibition of three physiologically relevant CA isozymes.17 Following the discovery that 2,6-dichloro-N-[2-(cyclopropanecarbonylamino)benzothiazol-6-yl] benzamide exhibited excellent in vivo inhibitory effect on tumour growth, a compound library was synthesised for structure optimisation.18
2.3. Scaffolds for combinatorial libraries The construction on SASRIN (super acid sensitive resin) of an L -proline scaffold that enforces a defined beta-turn loop for RGD has been reported.10
Sets of isomeric thiazole derivatives have been synthesised in a parallel iterative solution-phase synthesis approach guided by biological results and computeraided design and analysis, leading to highly active isomeric NPY5 receptor ligands.19
A reliable and efficient way for the synthesis of N9-alkylated purine library scaffolds, using tetrabutylammonium fluoride (TBAF) to accelerate the N9-alkylation of purine derivatives, has been reported. These mild reaction conditions permitted the use in combinatorial reactions in microtiter plates followed by in situ screening for the discovery of potent sulphotransferase inhibitors.11
Novel 3-thio-1,2,4-triazoles have been obtained via a solution-phase parallel synthesis strategy, affording potent non-peptidic agonists for the human somatostatin receptor subtypes 2 and 5.20
2.4. Solid-phase supported reagents Osmium tetroxide has been immobilised onto a shortlength PEGylated ionic polymer, which exhibited excellent catalytic performance in OsO4-catalysed asymmetric dihydroxylation.12 A range of alkyl spacer-tethered 1,2- and 1,3-diols have been prepared from commercially available Merrifield resin and (4-chloromethyl)phenylpentyl-polystyreneco-divinylbenzene. The utility of these resin-bound diols as supports for the Ti(IV)-catalysed Diels–Alder reaction has been described.13 The initial synthesis of UK-427,857 (Maraviroc), a potent antagonist of the CCR5 receptor, has been described including the preparation of 4,4-difluorocyclohexanoic acid and amide coupling utilising a polymer supported reagent.14 Polymer-supported chiral phosphinooxazolidine (POZ) ligands and cationic palladium-POZ catalysts have been prepared. The former ligands were used in the Pd-catalysed asymmetric allylic alkylation, while the latter catalysts were used in Diels–Alder chemistry.15 2.5. Novel resins, linkers and techniques No papers this month. 2.6. Library applications Non-steroidal mimetics of mifepristone and progesterone are important templates for modulation of the progesterone receptor and thus unexplored, synthetically
In a three-step sequence, an array of angularly fused polycyclic heterocycles with coumarin, benzofuran and pyridine rings were synthesised, fully characterised and screened for anti-microbial, anti-inflammatory and analgesic activities.21 Novel inhibitors of human dipeptidyl peptidase I (hDPPI, cathepsin C, EC 3.4.14.1) have been discovered via screening of a one-bead-two-compounds library of semicarbazide derivatives.22 A library of polyamine–peptide conjugates based around some previously identified inhibitors of trypanothione reductase have been synthesised by parallel solidphase chemistry and screened.23 Nucleoside bases have been constructed on Merrifield resin by sequential displacement of purine dichloride with amines, and after detachment, the purine analogues were condensed with D ,L -ribofuranoside compounds by the Vorbru¨ggen method and tested for activity against HIV-1 in PBM cells.24 A chemical library of substituted dihydropteridinones has been screened to identify a non-toxic, cell permeable, and reversible inhibitor of the RNAi pathway in human cells.25 References 1. Ding, B. et al. Organic Letters 2004, 6 (20), 3433–3436. 2. Bugaut, A. et al. Angew. Chem., Int. Ed. 2004, 43 (24), 3144–3147. 3. Belokon, Y. N. et al. Tetrahedron Lett. 2005, 46 (26), 4483–4486. 4. Jeon, M.-K. et al. Tetrahedron Lett. 2005, 46 (30), 4979–4983.
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Further reading Papers on combinatorial chemistry or solid-phase synthesis from other journals Nold, M.; Koch, K.; Wennemers, H. Acid-rich peptides are prone to damage under fenton conditions - split-and-mix libraries for the detection of selective peptide cleavage. Synthesis 2005 (9), 1455–1458. Lovrinovic, M.; Niemeyer, C. M. DNA microarrays as decoding tools in combinatorial chemistry and chemical biology. Angewandte Chemie, International Edition 2005, 44 (21), 3179–3183. Kumar, A.; Koul, S.; Razdan, T. K.; Andotra, C. S. A single pot synthesis of new dimeric 2-phenyl-10,3a-dihydro-1,3,4oxadiazolino[3,2-a]quinazolin-6-ols. Journal of Heterocyclic Chemistry 2005, 42 (4), 487–491. Corbett, P. T.; Sanders, J. K. M.; Otto, S. Competition between receptors in dynamic combinatorial libraries: amplification of the fittest? Journal of the American Chemical Society 2005, 127 (26), 9390–9392. Corbett, P. T.; Tong, L. H.; Sanders, J. K. M.; Otto, S. Diastereoselective amplification of an induced-fit receptor from a dynamic combinatorial library. Journal of the American Chemical Society 2005, 127 (25), 8902–8903.
Patek, M.; Weichsel, A. S.; Drake, B.; Smrcina, M. Solidphase synthesis of disubstituted 1,3-dihydro-2H-imidazol2-ones. Synlett 2005 (8), 1322–1324. Nielsen, T. E.; Meldal, M. Highly efficient solid-phase oxidative cleavage of olefins by OsO4-NaIO4 in the intramolecular N-acyliminium Pictet-Spengler reaction. Organic Letters 2005, 7 (13), 2695–2698. Tajbakhsh, M.; Hosseinzadeh, R.; Sadatshahabi, M. Synthesis and application of 2,6-dicarboxy pyridinium fluorochromate as a new solid-phase oxidant. Synthetic Communications 2005, 35 (11), 1547–1554. Sagara, Y.; Mitsuya, M.; Uchiyama, M.; Ogino, Y.; Kimura, T.; Ohtake, N.; Mase, T. Discovery of 2-aminothiazole-4carboxamides, a novel class of muscarinic M3 selective antagonists, through solution-phase parallel synthesis. Chemical & Pharmaceutical Bulletin 2005, 53 (4), 437–440. West, K. R.; Bake, K. D.; Otto, S. Dynamic combinatorial libraries of disulfide cages in water. Organic Letters 2005, 7 (13), 2615–2618. Dothager, R. S.; Putt, K. S.; Allen, B. J.; Leslie, B. J.; Nesterenko, V.; Hergenrother, P. J. Synthesis and identification of small molecules that potently induce apoptosis in melanoma cells through G1 cell cycle arrest. Journal of the American Chemical Society 2005, 127 (24), 8686–8696. Gendre, F.; Yang, M.; Diaz, P. Solid-phase synthesis of diaryl sulfides: direct coupling of solid-supported aryl halides with thiols using an insoluble polymer-supported reagent. Organic Letters 2005, 7 (13), 2719–2722. Guo, H.; Wang, Z.; Ding, K. PEG-polymer-supported liquidphase combinatorial synthesis of structurally diverse 2,3dihydro-4-pyridones. Synthesis 2005 (7), 1061–1068. Ohno, H.; Tanaka, H.; Takahashi, T. Solid-supported sulfonylhydroxylamine as an effective N-aminating agent of anilines. Synlett 2005 (7), 1191–1194. Houghten, R. A.; Yu, Y. ‘‘Volatilizable’’ supports for highthroughput organic synthesis. Journal of the American Chemical Society 2005, 127 (24), 8582–8583. Jian, H.; Tour, J. M. Preparative fluorous mixture synthesis of diazonium-functionalized oligo(phenylene vinylene)s. Journal of Organic Chemistry 2005, 70 (9), 3396–3424. Gachkova, N.; Cassel, J.; Leue, S.; Kann, N. The solid-phase Nicholas reaction: scope and limitations. Journal of Combinatorial Chemistry 2005, 7 (3), 449–457. Fuchi, N.; Doi, T.; Takahashi, T. A library synthesis of pyrazoles by azomethine imine cycloaddition to the polymer-supported vinylsulfone. Chemistry Letters 2005, 34 (3), 438–439. Krattiger, P.; Wennemers, H. Water-soluble diketopiperazine receptors - selective recognition of arginine-rich peptides. Synlett 2005 (4), 706–708. Martinez-Teipel, B.; Teixido, J.; Pascual, R.; Mora, M.; Pujola, J.; Fujimoto, T.; Borrell, J. I.; Michelotti, E. L. 2Methoxy-6-oxo-1,4,5,6-tetrahydropyridine-3-carbonitriles: versatile starting materials for the synthesis of libraries with diverse heterocyclic scaffolds. Journal of Combinatorial Chemistry 2005, 7 (3), 436–448. Ying, L.; Liu, R.; Zhang, J.; Lam, K.; Lebrilla, C. B.; GervayHague, J. A topologically segregated one-bead-one-compound combinatorial glycopeptide library for identification of lectin ligands. Journal of Combinatorial Chemistry 2005, 7 (3), 372–384. Fancelli, D.; Berta, D.; Bindi, S.; Cameron, A.; Cappella, P.; Carpinelli, P.; Catana, C.; Forte, B.; Giordano, P.; Giorgini, M. L.; Mantegani, S.; Marsiglio, A.; Meroni, M.; Moll, J.; Pittala, V.; Roletto, F.; Severino, D.; Soncini, C.; Storici, P.; Tonani, R.; Varasi, M.; Vulpetti, A.; Vianello, P. Potent and selective Aurora inhibitors identified by the expansion of a novel scaffold for protein kinase inhibition. Journal of Medicinal Chemistry 2005, 48 (8), 3080–3084.