The exploration of macrocycles for drug discovery - An underexploited structural class

Nature Reviews Drug Discovery

Volumn 7, Issue 7, 2008, Pages 608-624

  Driggers, Edward M ^a   Hale, Stephen P ^a   Lee, Jinbo ^a   Terrett, Nicholas K ^a  

^a Ensemble Discovery   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIBIOTIC AGENT; ANTIFUNGAL AGENT; ANTINEOPLASTIC AGENT; AVERMECTIN; AVERMECTIN DERIVATIVE; BETA SECRETASE INHIBITOR; CILUPREVIR; CYCLIN DEPENDENT KINASE INHIBITOR; CYCLOSPORIN A; EPOTHILONE B; ERYTHROMYCIN; IMMUNOMODULATING AGENT; IXABEPILONE; MACROCYCLIC COMPOUND; MACROLIDE; MATRIX METALLOPROTEINASE INHIBITOR; NATURAL PRODUCT; REBECCAMYCIN; RIFAMPICIN; RIFAMPICIN DERIVATIVE; RUBOXISTAURIN; SERINE PROTEINASE INHIBITOR; SPIRAMYCIN; TACROLIMUS; TELAPREVIR; TEMSIROLIMUS; THROMBIN INHIBITOR; TUBERCULOSTATIC AGENT; UNINDEXED DRUG; VANCOMYCIN; VANCOMYCIN DERIVATIVE;

BINDING AFFINITY; CONFORMATIONAL TRANSITION; DRUG BIOAVAILABILITY; DRUG CONFORMATION; DRUG DESIGN; DRUG EFFICACY; DRUG MECHANISM; DRUG PENETRATION; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG RESEARCH; DRUG STABILITY; DRUG SYNTHESIS; DRUG TARGETING; ENZYME INHIBITION; HUMAN; MOLECULAR STABILITY; NONHUMAN; PRIORITY JOURNAL; REVIEW; STEREOCHEMISTRY; STRUCTURE ACTIVITY RELATION;

ANIMALS; BIOLOGICAL PRODUCTS; CELL MEMBRANE PERMEABILITY; DRUG DESIGN; HUMANS; MACROCYCLIC COMPOUNDS;

EID: 46449115901     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd2590     Document Type: Review

References (102)

1. Breirbauer, R. et al. From protein domains to drug candidate - natural products as guiding principles in the design and synthesis of compound libraries. Angew. Chem. Int. Ed. 41, 2878-2890 (2002).
2. Lipinski, C. A., Lombardo, F., Dominy, B. W. & Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 23, 3-25 (1997).
3. Demain. A. L. & Fang, A. The natural functions or secondary metabolites. Adv. Biochem. Eng. Biotechnol. 69, 2-39 (2000).
4. Wessjohann, L. A. et al. What can a chemist learn from nature's macrocycles? A brief, conceptual view. Mol. Divers. 9, 171-186 (2005).
5. Williams, D. H., Stone, M. J., Hauck, P. R. & Pahman, S. K. Why are secondary metabolites (natural products) biosynthesized? J. Nat. Prod. 52, 1189-1208 (1989).
6. Stone, M. J. & Williams, D. H. On the evolution of functional secondary metabolites (natural products). Mol. Microbiol. 6, 29-34 (1992).
7. Katz, E. & Demain, A. L. The peptide antibiotics of Bacillus: chemistry, biogenesis, and possible functions. Bacteriol. Rev. 41, 449-474 (1977).
8. Mulvenna, J. P. et al. Discovery of cyclotide-like protein sequences in graminaceous crop plants: Ancestral precursors of circular proteins? Plant Cell 18, 2134-2144 (2006).
9. McArdle, B. M., Campitelli, M. R., Quinn, R. J. A common protein fold topology shared by flavonoid biosynthetic enzymes and therapeutic targets. J. Nat. Prod. 69, 14-17 (2006).
10. Blondeau, J. M. The evolution and role of macrolides in infectious diseases. Expert Opin. Pharmocother. 3, 1131-1151 (2002).
11. Nielsen, J. Combinatorial synthesis of natural product libraries. Curr. Opin. Chem. Biol. 6, 297-305 (2002).
12. Wessjohann, L. A. Synthesis of natural product-based compound libraries. Curr. Opin. Chem. Biol. 4, 303-309 (2000).
13. Jensen, P. R., Williams, P. G., Oh, D.-C., Zeigler, L. & Fenical, W. Species-specific secondary metabolite production in marine actinomycetes of the genus Salinispora. Appl. Environ. Microbiol. 73, 1146-1152 (2007).
14. Udwary D. W. et al. Genome sequencing reveals complex secondary metabolome in the marine actinomycete Salinispora tropica. Proc. Natl. Acad. Sci. USA 104, 10376-10381 (2007).
15. Jenke-Kodama, H., Sandmann, A., Mueller, R. & Dittmann, E. Evolutionary implications of bacterial polyketide synthases. Mol. Biol. Evol. 22, 2027-2039 (2005).
16. Kim, T. K., Hewavitharana, A. K., Shaw, P. N. & Fuerst, J. A. Discovery of a new source of rifamycin antibiotics in marine sponge actinobacteria by phylogenetic prediction. Appl. Environ. Microbiol. 72, 2118-2125 (2006).
17. Merck. The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals, Fourteenth Edition (eds O'Neil, M. J., Heckelman, P. E., Koch, C. B. & Roman, K. J.) (Merck & Co., Inc., Whitehouse Station, NJ, USA, 2006).
18. Newman, D. J., Cragg, G. M. & Snader, K. M. Natural products as sources of new drugs over the period 1981-2002. J. Nat. Prod. 66, 1022-1037 (2003).
19. Choi, J., Chen, J., Schreiber, S. L. & Clardy, J. Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Science 273, 239-242 (1996).
20. Nghiem, P., Pearson, G. & Langley, R. G. Tacrolimus and primecrolimus: from clever prokaryotes to inhibiting calcineurin and treating atopic dermatitis. J. Am. Acad. Dermatol. 46, 228-241 (2002).
21. Butler, M. S. Natural products to drugs: Natural product derived compounds in clinical trials. Nat. Prod. Rep. 22, 162-195 (2005).
22. Faivre, S., Kroemen G. & Raymond, E. Current development of MTOR inhibitors as anticancer agents. Nature Rev. Drug. Discov. 5 671-688 (2006).
23. Schreiber, S. L. Immunophilin-sensitive protein phosphatase action in cell signaling pathways. Cell 70, 365-368 (1992).
24. Schreiber, S. L. & Crabtree, G. R. The mechanism of action of cyclosporin A and FK506. Immunol. Today 13, 136-142 (1992).
25. Feyen, F., Cachoux, F., Gertsch, J., Wartmann, M. & Altmann, K.-H. Epothilones as lead structures for the synthesis-based discovery of new chemotypes for microtubule stabilization. Accounts Chem. Res. 41, 21-31 (2008).
26. Nogales, E., Wolf, S. G., Khan, I. A., Luduena, R. F. & Dowring, K. H. Structure of tubulin at 6.5 A and location of the taxol binding site. Nature 315, 424-427 (1995).
27. Mani, S. et al. Ixabepilone: Antimitotic drug: microtubule-stabilizing agent: Epothilone. Drug Future 32, 1033-1039 (2007).
28. Madiraju, C. et al. Tubulin assembly, taxoid site binding, and celluldr effects of the microtubule-stabilizing agent dictyostatin. Biochemistry 44, 15053-15063 (2005).
29. Hamel, E. et al. Synergistic effects of peloruside A and laulimalide with taxoid site drugs, but not with each other, on tubulin assembly. Mol. Pharmacol. 70, 1555-1564 (2006).
30. Dabydeen, D. A. et al. Comparison of the activities of the truncated halichondrin B analog NSC 707389 (E7389) with those of the parent compound and a proposed binding site on tubulin. Mol. Pharmacol. 70, 1866-1875 (2006).
31. Schlunzen, F. et al. Structural basis for the interaction of antibiotics with the peptidyl transferase center in eubacteria. Nature 413, 814-821 (2001).
32. Tenson, T., Lovmar, M. & Ehrenerg, M. The mechanism of action of macrolides, lincosamides, and stieptogramin B reveals nascent peptide exit path in the ribosome. J. Mol. Biol. 330, 1005-1014 (2003).
33. Fusetani, N., Matsunaga, S., Matsumoto, H. & Takebayashi, Y. Bioactive marine metabolites. 33. Cyclotheconamides, potent thrombin inhibitors, from a marine sponge Theonella sp. J. Am. Chem. Soc. 112 7053-7054 (1990).
34. Maryanoff, B. E. Inhibitors of serine proteases as potential therapeutic agents: The road from thrombin to tryptase to cathepsin G. J. Med. Chem. 47, 769-787 (2007).
35. Brauer, A. B., McBride, J. D., Kelly, G., Matthews, S. J. & Leatherbarrow, R. J. Resisting degradation by human elastase: commonality of design features shared by 'canonical' plant and bacterial macrocyclic protease inhibitor scaffolds. Bioorg. Med. Chem. 15 4618-4628 (2007).
36. Greco, M. N. & Maryanoff, B. E. Macrocyclic inhibitors of serine proteases. Adv. Amino Acid Mimetics Peptidomimetics 1, 41-76 (1997).
37. Matsumori, N., Yamaji, N., Matsuoka, S., Oishi, T. & Murata, M. Amphotericin B covalent dimers forming sterol-dependent ion-permeable membrane channels. J. Am. Chem. Soc. 124, 4180-4181 (2002).
38. Wender, P. A. et al. The design, computer modeling, solution structure, and biological evaluation of synthetic analogs of bryostatin 1. Proc. Natl Acad. Sci. USA 95, 6624-6629 (1998).
39. Koehn, F. F. & Carter, G. T. The evolving role of natural products in drug discovery. Nature Rev. Drug Disc. 4, 206-220 (2005).
40. Somers, P. K., Wandless, T. J. & Schreiber S. L. Synthesis and analysis of 506BD, a high affinity ligand for the immunophilin FKBP. J. Am. Chem. Soc. 113, 8045-8056 (1991).
41. Bayle, J. H. et al. Rapamycin analogs with differential binding specificity permit orthogonal control of protein activity. Chem. Biol. 13, 99-107 (2006).
42. Fehr, T. et al. Antascomicins A, B, C, D. E Novel FKBP12 binding compounds from a Micromonospora strain. J. Antibiot. (Tokyo) 49, 230-233 (1996).
43. Navia, M. A. & Chaturvedi, P. R. Design principles for orally bioavailable drugs. Drug Discov. Today 1, 179-189 (1996).
44. Loll, P. J., Bevivino, A. E., Korty, B. D. & Axelsen, P. H. Simultaneous recognition of a carboxylate-containing ligand and an intramolecular surrogate ligand in the crystal structure of an asymmetric vancomycin dimer. J. Am. Chem. Soc. 119, 1516-1522 (1997).
45. Nicolaou, K. C. et al. Solid- and solution phase synthesis of vancomycin and vancomycin analogues with activity against vancomycin-resistant bacteria. Chem. Eur. J. 7, 3798-3823 (2001).
46. Nicolaou, K. C. et al. Synthesis and biological evaluation of vancomycin dimers with potent activity against vancomycin-resistant bacteria: Target-accelerated combinatorial synthesis. Chem. Eur. J. 7, 3824-3843 (2001).
47. Allen, N. E. & Nicas, T. I. Mechanism of action of oritavancin and related glycopeptide antibiotics. FEMS Microb. Rev. 26, 511-532 (2003).
48. Williams, D. H. & Bardsley, B. The vancomycin group of antibiotics and the fight against resistant bacteria. Angew. Chem. Int. Ed. 38 1173-1193 (1999).
49. Perni, R. B. et al. Preclinical profile of VX-950, a potent, selective, and orally bioavailable inhibitor of hepatitis C virus NS3-4B serine protease. Antimicrob. Agents Chemother. 50, 899-909 (2006).
50. Tsantrizos, Y. S. et al. Macrocyclic inhibitors of the NS3 protease as potential therapeutic agents of hepatitis C virus infection. Angew Chem. Int. Ed. 42, 1356-1360 (2003).
51. Llinas-Brunet, M. et al. of Structure - activity study on a novel series of macrocyclic inhibitors of the hepatitis C virus NS3 protease leading to the discovery of BILN 2061. J. Med. Chem. 47, 1605-1608 (2004).
52. Lamarre, D. et al. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature 426 186-189 (2003).
53. Kim, Y.-K. et al. Relationship of stereochemical and skeletal diversity of small molecules to cellular measurement space. J Am. Chem. Soc. 126, 14740-14745 (2004).
54. Jirousek, M. R. et al. (S)-13-[(Dimethylamino)methyl]- 10, 11, 14, 15-tetrahydro-4, 9:16,21 -dimetheno-1H, 13H-dibenzole, [e, k]pyrrolo [3,4-h][1, 4, 13]oxadiazacyclohexadecene- 1,3 (2H)-dione (LY333531) and related analogues: Isozyme selective inhibitors of protein kinase Co. J. Med. Chem. 39, 2664-2671 (1996).
55. Bartlett, S. et al. Comparison of the ATP binding sites of protein kinases using conformationally diverse bisindolylmaleimides. J. Am. Chem. Soc. 127, 11699-11708 (2005).
56. Rezai, T et al. Testing the conformational hypothesis of passive membrane permeability using synthetic cyclic peptide diastereomers. J. Am. Chem. Soc. 128, 2510-2511 (2006).
57. Rezai, T. et al. Conformational flexibility, internal hydrogen bonding, and passive membrane permeability: Successful in silica prediction of the relative permeabilities of cyclic peptides. J. Am Chem. Soc. 128. 14073-14080 (2006).
58. Stachel, S. J. et al. Macrocyclic inhibitors of β-secretase: functional activity in an animal model. J. Med. Chem. 49, 6147-6150 (2006).
59. Wiley, R. A. & Rich, D. H. Peptidomimetics derived from natural products. Med. Res. Rev. 13, 327-384 (1993).
60. Chen, K. X. et al. Novel potent hepatitis C virus NS3 serine protease inhibitors derived from proline-based macrocycles. J. Med. Chem. 49, 995-1005 (2006).
61. Bell, J. M. et al. 3-Aminopyrrolidinones farnesyltransferase inhibitors: Design of macracyclic compounds with improved pharmacokinetics and excellent cell potency, J. Med. Chem. 45 2388-2409 (2002).
62. Reid, R. C., Kelso, M. J., Scanlon, M. J. & Fairlie, D. P. Conformationally constrained macrocycles that mimic tripeptide β-strands in water and aprotic solvents. J. Am Chem. Soc. 124 5673-5683 (2002).
63. Jackson, S. et al. Template-constrained cyclic peptides: Design of high-affinity ligands for GPIIb/IIIa J. Am. Chem. Soc. 116: 3220-3230 (1994).
64. Ruggli, P. A ring with triple bonds. Justus Liebigs Ann. Chem. 392, 92-100 (1912).
65. Wessjohann, L. A. & Ruijter, E. Strategies for total and diversity-oriented synthesis of natural-product (-like) macrocycles. Top. Curr. Chem. 243, 137-184 (2005).
66. Gradillas, A. & Perez-Castells, J. Macrocyclization by ring-closing metathesis in the total synthesis of natural products: Reaction conditions and limitations. Angew. Chem. Int. Ed. 45, 6086-6101 (2006).
67. Wessjohann, L. A. & Ruijter, E Macrocycles rapidly produced by multiple multicomponent reactions including bifunctional building blocks (MiBs). Mol. Divers. 9, 159-169 (2005).
68. Gerbeleu, N. V. & Arion, V. B. in Complex Formation and Stereochemistry of Coordination Compounds (ed. Buslaev, Y.) 133-204 (Nova Science Publishers, New York, NY, USA, 1996).
69. Meutermans, W. D. F. et al. Difficult macrocyclizations: New strategies for synthesizing highly strained cyclic tetrapeptides. Org. Lett. 5, 2711-2714 (2003).
70. David, O. et al. Intramolecular Staudinger ligation: A powerful ring-closure method to form medium-sized lactams. Angew. Chem. Int. Ed. 42, 4373-4375 (2003).
71. Schmidt, D. R., Kwon, O. & Schreiber, S. L. Macrolactones in diversity-oriented synthesis: Preparation of a pilot library and exploration of factors controlling macrocyclization. J. Comb. Chem. 6, 286-292 (2004).
72. Marsault, E. et al. Discovery of a new class of macrocyclic antagonists to the human motilin receptor. J. Med. Chem. 49, 7190-7197 (2006).
73. Gartner, Z. J. et al. DNA-templated organic synthesis and selection of a library of macrocycles. Science 305, 1601-1605 (2004).
74. Driggers, E. M. et al. DNA-programmed assembly, characterization, and selection of small molecule libraries. 232nd ACS National Meeting, San Francisco, CA, United States Sept. 10-14, 2006. ACS web site [online], (2006).
75. Kino, T. et al. FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physicochemical and biological characteristics. J. Antibiot. 40, 1249-1255 (1987).
76. Kim, B.-J. et al. Phylogenetic analysis of the genera Streptomyces and Kitasatospora based on partial RNA polymerase β-subunit gene (rpoB) sequences. Int. J. Syst. Evol. Microbiol. 54, 593-598 (2004).
77. Ikeda, Y., Schultz, L. W., Clardy, J. & Schreiber, S. L. Structural basis for peptidomimicry by a natural product. J. Am. Chem. Soc. 116, 4143-4144 (1994).
78. Clardy, J. Structural studies on FK-506, cyclosporin A and their immunophilin complexes. Perspect. Drug Discov. Design 2, 127-144 (1994).
79. Seiwert, S. et al. Preclinical characteristics of ITMN-191, an orally active inhibitor of the HCV NS3/4A protease nominated for preclinical development. Digestive Disease Week 2006, Los Angeles, USA, May 21-24 2006. Array Biopharma web site [online], (2006).
80. Dinsmore, C. J. et al. Conformational restriction of flexible ligands guided by the transferred noe experiment: Potent macrocyclic inhibitors of farnesyltransferase. J. Am. Chem. Soc. 123, 2107-2108 (2001).
81. Udugamasooriya, G., Saro, D. & Spaller, M. R. Bridged peptide macrocycles as ligands for PDZ domain proteins. Org. Lett. 7 1203-1206 (2005).
82. Tao, Z.-F. et al. Structure-based design, synthesis, and biological evaluation of potent and selective macrocyclic checkpoint kinase 1 inhibitors. J. Med. Chem. 50, 1514-1527 (2007).
83. Shi, Z.-D. et al. A novel macrocyclic tetrapeptide mimetic that exhibits low-picomolar Grb2 SH2 domain-binding affinity. Biochem. Biophys. Res. Commun. 310, 378-383 (2003).
84. Wei, C.-Q., Li, B., Guo, R., Yang, D. & Burke, T. R. Development of a phosphatase-stable phosphotyrosyl mimetic suitably protected for the synthesis of high-affinity Grb2 SH2 domain-binding ligands. Bioorg. Med. Chem. Lett. 12, 2781-2784 (2002).
85. Zhang, H.-C. et al. Novel bis(indolyl)maleimide pyridinophanes that are potent, selective inhibitors of glycogen synthase kinase-3. Bioorg. Med. Chem. Lett. 17, 2863-2868 (2007).
86. Kawanishi, N. et al. Structure-based drug design of a highly potent CDK1,2,4,6 inhibitor with novel macrocyclic quinoxalin-2-one structure. Bioorg. Med. Chem. Lett. 16, 5122-5126 (2006).
87. Lucking, U. et al. Macrocyclic aminopyrimidines as multitarget CDK and VEGF-R inhibitors with potent antiproliferative activities. ChemMedChem 2, 63-77 (2007).
88. Cisar, J. S. et al. Exploiting ligand conformation in selective inhibition of non-ribosomal peptide synthetase amino acid adenylation with designed macrocyclic small molecules. J. Am. Chem. Soc. 129, 7752-7753 (2007).
89. Cherney, R. J. et al. Macrocyclic amino carboxylates as selective MMP-8 inhibitors. J. Med. Chem. 41, 1749-1751 (1998).
90. Hu, X. et al. Structure-based design of a macrocyclic inhibitor for peptide deformylase. J. Med. Chem. 46, 3771-3774 (2003).
91. Hu, X. et al. Macrocyclic inhibitors for peptide deformylase: A structure-activity relationship study of the ring size. J. Med. Chem. 47, 4941-4949 (2004).
92. 1 dipeptide mimetics. J. Med. Chem. 34, 887-900 (1991).
93. 1'-linked macrocyclic human renin inhibitors. J. Med Chem. 34, 2692-2701 (1991).
94. Weber, A. E. et al. Highly potent, orally active diester macrocyclic human renin inhibitors. J. Med. Chem. 35, 3755-3773 (1992).
95. Yang, L., Weber, A. E., Greenlee, W. J. & Patchett, A. A. Macrocyclic renin inhibitors: Synthesis of a subnanomolar, orally active cysteine derived inhibitor. Tetrahedron Lett. 34, 7035-7038 (1993).
96. Tyndall, J. D. A. et al., Synthesis, stability, antiviral activity, and protease-bound structures of substrate-mimicking constrained macrocyclic inhibitors of HIV-1 protease. J. Med. Chem. 43, 3495-3504 (2000).
97. Reid, R. C. et al. Countering cooperative effects in protease inhibitors using constrained β-strand-mimicking templates in focused combinatorial libraries. J. Med. Chem. 47, 1641-1651 (2004).
98. Smith, R. A. et al. Design, synthesis, and activity of conformationally-constrained macrocyclic peptide-based inhibitors of HIV protease. Bioorg. Med. Chem. Lett. 4, 2217-222 (1994).
99. Chen, I J. et al. Synthesis and activity of conformationally-constrained macrocyclic norstatine-based inhibitors of HIV protease. Bioorg. Med. Chem. Lett. 6, 435-438 (1996).
100. Podlogar, B. L. et al. Design, synthesis, and conformational analysis of a novel macrocyclic HIV-protease inhibitor. J. Med. Chem. 37, 3684-3692 (1994).
101. Marsault, E. et al. Potent macrocyclic antagonists to the motilin receptor presenting novel unnatural amino acids. Bioorg. Med. Chem. Lett. 17, 4187-4190 (2007).
102. Xiao, O. & Pei, D. High-throughput synthesis and screening of cyclic peptide antibiotics. J. Med. Chem. 50, 3132-3137 (2007).