Epothilone, a myxobacterial metabolite with promising antitumor activity

Anticancer Agents from Natural Products

Volumn , Issue , 2005, Pages 413-450

  Höfle, Gerhard ^a   Reichenbach, Hans ^a  

^a HELMHOLTZ CENTRE FOR INFECTION RESEARCH   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

FUNCTIONAL GROUPS; MAMMALS; METABOLITES; PATENTS AND INVENTIONS; SPECTROSCOPIC ANALYSIS;

ABSOLUTE CONFIGURATION; ANTI-FUNGAL ACTIVITY; ANTI-TUMOR ACTIVITIES; CULTURE COLLECTION; CYTOTOXIC COMPOUNDS; SECONDARY METABOLITES; SORANGIUM CELLULOSUM; SPECTROSCOPIC METHOD;

X RAY CRYSTALLOGRAPHY;

EID: 84937419962     PISSN: None     EISSN: None     Source Type: Book    
DOI: None     Document Type: Chapter

References (230)

1. Höfle, G., Biologically active secondary metabolites from myxobacteria — isolation and structure elucidation, in Scientific Annual Report of the GBF, Walsdorff, H.-J., Ed., Gesellschaft für Biotechnologische Forschung, Braunschweig, 1991, 65-68.
2. Gerth, K. et al., Epothilones A and B: Antifungal and cytotoxic compounds from Sorangium cellulosum (Myxobacteria), J. Antibiot., 49, 560, 1996.
3. Höfle, G. et al., Epothilone A and B — Novel 16-membered macrolides with cytotoxic activity: isolation, crystal structure, and conformation in solution, Angew. Chem. Int. Ed., 35, 1567, 1996.
4. Hardt, I.H. et al., New natural epothilones from Sorangium cellulosum, strains So ce90/B2 and So ce90/D13: isolation, structure elucidation, and SAR studies, J. Nat. Prod., 64, 847, 2001.
5. Höfle, G. et al., German Patent 4138042, filed Nov. 11, 1991, granted Oct. 14, 1993; World Patent 9310121 filed Nov. 19, 1992.
6. Reichenbach, H. and Höfle, G., Biologically active secondary metabolites from myxobacteria, Biotech. Adv., 11, 219, 1993;
7. Höfle, G. and Reichenbach, H., The biosynthetic potential of the myxobacteria, in Sekundärmetabolismus bei Mikroorganismen, Kuhn, W. and Fiedler, H.-P., Eds., Attempto, Tübingen, 1995, 61-78;
8. Reichenbach, H. and Höfle, G., Myxobacteria as producers of secondary metabolites, in Drug Discovery from Nature, Grabley, S. and Thiericke, R., Eds., Springer, Berlin, 1999, 149-179.
9. Lavelle, F., What’s new about new tubulin/microtubules binding agents? Exp. Opin. Invest. Drugs, 4, 771, 1995.
10. Bollag, D.M. et al., Epothilones, a new class of microtubule-stabilizing agents with a Taxol-like mechanism of action, Cancer Res., 55, 2325, 1995.
11. Gerth, K. et al., Myxobacteria, proficient producers of novel natural products with various biological activities past and future biotechnological aspects with the focus on the genus Sorangium, J. Biotechnol., 106, 233, 2003.
12. Nicolaou, K.C., Roschangar, F., and Vourloumis, D., Chemical biology of epothilones, Angew. Chem. Int. Ed. Engl. 37, 2014, 1998;
13. Mulzer, J., Martin, H.J., and Berger, M., Progress in the synthesis of chiral heterocyclic natural products: epothilone B and tartrolon B, J. Heterocyclic Chem., 36, 1421, 1999;
14. G. Höfle, Epothilone — a natural product on the road to becoming a medicine, in Scientific Annual Report of the GBF, Jonas, R., Ed., 1999/2000, 21;
15. Altmann, K.-H. et al., Epothilones and their analogs — potential new weapons in the fight against cancer, Chimia, 54, 612, 2000;
16. Altmann, K.-H., Wartmann, M., and O’Reilly, T., Epothilones and related structures — a new class of microtubule inhibitors with potent in vivo antitumor activity, Biochim. Biophys. Acta, 1470, M79, 2000;
17. Mulzer, J., Epothilone B and its derivatives as novel antitumor drugs: total and partial synthesis and biological evaluation, Monatshefte für Chemie, 131, 205, 2000;
18. Winssinger, N. and Nicolaou, K.C., Epothilones and sarcodictyns: from combinatorial libraries to designed analogs, ACS Symposium Series 796, Anticancer Agents, Frontiers in Cancer Therapy, Ojima, I., et al., Eds., American Chemical Society, 2001, 148;
19. Altmann, K.-H., Microtubule-stabilizing agents: a growing class of important anticancer drugs, Curr. Opin. Chem. Biol., 5, 424, 2001;
20. Stachel, S.J., Biswas, K., and Danishefsky, S.J., The epothilones, eleutherobins, and related types of molecules, Curr. Pharm. Design 7, 1277, 2001;
21. Nicolaou, K.C., Ritzén, A., and Namoto, K., Recent development in the Epothilone, a Myxobacterial Metabolite with Promising Antitumor Activity 443 chemistry, biology and medicine of the epothilones, Chem. Commun., 1523, 2001;
22. Flörsheimer, A. and Altmann, K.-H., Epothilones and their analogs — a new class of promising microtubule inhibitors, Expert Opin. Ther. Patents, 11, 951, 2001;
23. Wartmann, M. and Altmann, K.-H., The biology and medicinal chemistry of epothilones, Curr. Med. Chem. AntiCancer Agents, 2, 123, 2002;
24. Borzilleri, R.M. and Vite, G.D., Epothilones: new tubulin polymerization agents in preclinical and clinical development, Drugs Future, 27, 1149, 2002;
25. Altmann, K.-H., Epothilone B and its analogs — a new family of anticancer agents, Med. Chem., 3, 149, 2003;
26. Mulzer, J. and Martin, H.J., Chem. Rec., 3, 258, 2004;
27. Lin, N., Brakora, K., and Seiden, M., BMS-247550 Bristol-Myers Squibb/GBF, Curr. Opin. Investig. Drugs, 4, 746, 2003;
28. Rivkin, A. et al., Application of ring-closing metathesis reactions in the synthesis of epothilones, J. Nat. Prod., 67, 139, 2004;
29. Goodin, S., Kane, M.P., and Rubin, E.H., Epothilones: mechanism of action and biological activity, J. Clin, Oncol., 10, 2015, 2004.
30. Reichenbach, H., Order Myxococcales, in Bergey’s Manual of Systematic Bacteriology, 2nd edition, Garrity, G., Ed., Springer, New York, 2004.
31. Myxobacteria II, Dworkin, M. and Kaiser, D., Eds., American Society for Microbiology, Washington, DC, 1993, 1-404
32. Höfle, G. et al., (GBF) German Patent 4211056, 1993.
33. K. Gerth, personal communication.
34. Gerth, K. et al., Studies on the biosynthesis of epothilones: hydroxylation of epo A and B to epothilones E and F, J. Antibiot., 55, 41, 2002.
35. Gerth, K. et al., Studies on the biosynthesis of epothilones: The biosynthetic origin of the carbon skeleton, J. Antibiot., 53, 1373, 2000.
36. Gerth, K. et al., Studies on the biosynthesis of epothilones: the PKS and epothilone C/D monooxygenase, J. Antibiot., 54, 144, 2001.
37. Reichenbach, H. et al., (GBF) German Patent 9647580 (1996).
38. Hofmann, H. et al., (Novartis) World Patent 9942602 (1999).
39. Hecht, H.-J. and Höfle, G., unpublished results; Crystallographic data of the structure have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-241333 and CCDC-241334 — copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: (+44)1223-336-033; e-mail: deposit@ccdc.cam.ac.uk].
40. Höfle, G. et al., unpublished results.
41. Straubing, R.M., Biopharmaceuticals of paclitaxel, in Taxol®, Science Application, Suffness, M., Ed., CRC Press, Boca Raton, FL, 1995, 238.
42. Chou, T.-C. et al., Desoxyepothilone B is curative against human tumor xenografts that are refractory to paclitaxel, Proc. Natl. Acad. Sci. USA, 95, 15798, 1998;
43. Lee, C.B. et al., Total synthesis and antitumor activity of 12,13-desoxyepothilone F: An unexpected solvolysis problem at C15, mediated by remote substitution at C21, J. Org. Chem., 65, 6525, 2000.
44. Tang, L. et al., Cloning and heterologous expression of the epothilone gene cluster, Science, 287, 640, 2000.
45. Julien, B. and Shah, S., Heterologous expression of epothilone biosynthetic genes in Myxococcus xanthus, Antimicrob. Agents Chemother., 46, 2772, 2002.
46. Lau, J. et al., Optimizing the heterologous production of epothilone D in Myxococcus xanthus, Biotechnol. Bioeng., 78, 280, 2002.
47. Arslanian, R.L. et al., Large-scale isolation and crystallization of epothilone D from Myxococcus xanthus cultures, J. Nat. Prod., 65, 570, 2002.
48. Regentin, R. et al., Nutrient regulation of epothilone biosynthesis in heterologous and native production strains, Appl. Microbiol. Biotechnol., 61, 451, 2003.
49. Frykman, S. et al., Modulation of epothilone analog production through media design, J. Ind. Microbiol. Biotechnol., 28, 17, 2002.
50. Molnar, I. et al., The biosynthetic gene cluster for the microtubule-stabilizing agents epothilones A and B from Sorangium cellulosum So ce90, Chem. Biol., 7, 97, 2000.
51. Julien, B. et al., Isolation and characterization of the epothilone biosynthetic gene cluster from Sorangium cellulosum, Gene, 249, 153, 2000.
52. Schupp, T. et al., World Patent 9966028-A (Dec. 23, 1999), (Novartis AG).
53. Julien, B. et al., World Patent 200031247-A (June 2, 2000), (Kosan Bioscience).
54. Walsh, C.T. and O’Connor, S.E., Polyketide-nonribosomal peptide epothilone antitumor agents: the EpoA, B, C subunits, J. Ind. Microbiol. Biotechnol., 30, 448, 2003.
55. Tang, L. et al., Elucidating the mechanism of cis double bond formation in epothilone biosynthesis, J. Am. Chem. Soc., 126, 46, 2004.
56. Arslanian, R.L. et al., A new cytotoxic epothilone from modified polyketide synthases heterologously expressed in Myxococcus xanthus, J. Nat. Prod., 65, 1061, 2002.
57. Starks, C.M. et al., Isolation and characterization of new epothilone analogs from recombinant Myxococcus xanthus fermentations, J. Nat. Prod., 66, 1313, 2003;
58. Boddy, C.N. et al., Precursordirected biosynthesis of epothilone in Escherichia coli, J. Am. Chem. Soc., 126, 7436, 2004.
59. Tang, L. et al., Generation of novel epothilone analogs with cytotoxic activity by biotransformation, J. Antibiot., 56, 16, 2003.
60. O’Connor, S.E., Walsh, C.T., and Liu, F., Biosynthesis of epothilone intermediates with alternate starter units: engineering polyketide-nonribosomal interfaces, Angew. Chem. Int. Ed., 42, 3917, 2003.
61. Schneider, T.L., Walsh, C.T., and O’Connor, S.E., Utilization of alternate substrates by the first three modules of the epothilone synthetase assembly line, J. Am. Chem. Soc., 124, 11272, 2002.
62. Chen, H. et al., Epothilone biosynthesis: assembly of the methylthiazolylcarboxy starter unit on the EpoB subunit, Chem. Biol., 8, 899, 2001.
63. O’Connor, S. E., Chen, H., and Walsh, C. T., Enzymatic assembly of epothilones: the epoC subunit and reconstitution of the epoA-ACP/B/C polyketide and nonribosomal peptide interfaces, Biochemistry, 41, 5685, 2002.
64. Schneider, T.L., Shen, B., and Walsh, C.T., Oxidase domains in epothilone and bleomycin biosynthesis: thiazoline to thiazole oxidation during chain elongation, Biochemistry, 42, 9722, 2003.
65. Lopez, J.V., Naturally mosaic operons for secondary metabolite biosynthesis: variability and putative horizontal transfer of discrete catalytic domains of the epothilone polyketide synthase locus, Mol. Gen. Genomics, 270, 420, 2003.
66. Nagano, S. et al., Crystal structures of epothilone D-bound, epothilone B-bound, and substrate-free forms of cytochrome P450epoK, J. Biol. Chem., 278, 44886, 2003.
67. Chou, T.-C. et al., Desoxyepothilone B: An efficacious microtubule-targeted antitumor agent with a promising in vivo profile relative to epothilone B, Proc. Natl. Acad. Sci. USA, 95, 9642, 1998.
68. Kowalski, R.J., Giannakakou, P., and Hamel, E., Desoxyepothilone B is curative against human tumor xenografts that are refractory to paclitaxel, J. Biol. Chem., 272, 2534, 1997.
69. Schinzer, D. et al., Synthesis and biological evaluation of Aza-epothilones, Chem. Bio. Chem., 1, 67, 2000.
70. Su, D.-S. et al., Structure–activity relationships of the epothilones and the first in vivo comparison with paclitaxel, Angew. Chem. Int. Ed., 36, 2093, 1997.
71. Höfle, G. et al., N-Oxidation of epothilone A–C and O-Acyl rearrangement to C-19-and C21-substituted epothilones, Angew. Chem. Int. Ed., 38, 1971, 1999.
72. Borzilleri, R.M. et al., A novel application of a Pd(0)-catalyzed nucleophilic substitution reaction to the regio-and stereoselective synthesis of lactam analogs of the epothilone natural products, J. Am. Chem. Soc., 122, 8890, 2000.
73. Sepp-Lorenzino, L. et al., The microtubule-stabilizing agents epothilones A and B and their desoxyderivatives induce mitotic arrest and apoptosis in human prostate cancer cells, Prostate Cancer Prost. Dis., 2, 41, 1999.
74. Nicolaou, K.C. et al., Total synthesis of oxazole-and cyclopropane-containing epothilone A analogs by the olefin metathesis approach, Chem. Eur. J. 3, 1957, 1997.
75. Nicolaou, K.C. et al., Total synthesis of oxazole-and cyclopropane-containing epothilone B analogs by the macrolactonization approach, Chem. Eur. J., 3, 1971, 1997.
76. Stachel, S.J. et al., On the interactivity of complex synthesis and tumor pharmacology in the drug discovery process: total synthesis and comparative in vivo evaluations of the 15-Aza epothilones, J. Org. Chem., 66, 4369, 2001.
77. Chou, T.-C. et al., The synthesis, discovery, and development of a highly promising class of microtubule stabilisation agents: curative effects of desoxyepothilones B and F against human tumor xenografts in nude mice, Proc. Natl. Acad. Sci. USA, 98, 8113, 2001.
78. Lee, F.Y.F. et al., BMS-247550: a novel epothilone analog with a mode of action similar to paclitaxel but possessing superior antitumor efficacy, Clin. Cancer Res., 7, 1429, 2001.
79. Wolff, A., Technau, A., and Brandner, G., Epothilone A induces apoptosis in neuroblastoma cells with multiple mechanisms of drug resistance, Int. J. Oncol., 11, 123, 1997.
80. Mühlradt, P.F. and Sasse, F., Epothilone B stabilizes microtubuli of macrophages like Taxol without showing Taxol-like endotoxin activity, Cancer Res., 57, 3344, 1997.
81. Kamath, K. and Jordan, M.A., Suppression of microtubule dynamics by epothilone B is associated with mitotic arrest, Cancer Res., 63, 6026, 2003.
82. Chen, J.G. and Horwitz, S.B., Differential mitotic responses to microtubule-stabilizing and -destabilizing drugs, Cancer Res., 62, 1935, 2002.
83. Iffert, R. and Sasse, F., Analyse des Apoptischen Zellkernzerfalls durch Bildverarbeitung, BIOforum, 22, 631, 1999.
84. Lichtner, R.B. et al., Subcellular distribution of epothilones in human tumor cells, Proc. Natl. Acad. Sci. USA, 98, 11743, 2001.
85. Klar, U. et al., Synthesis and biological activity of epothilones, ACS Symposium Series 796, Anticancer Agents, Frontiers in Cancer Therapy, Ojima, Iwao et al., Eds., American Chemical Society, 2001, 131–146.
86. Atadja, P., Isolation and characterisation of epothilone A resistant cells, Proc. Am. Assoc. Cancer Res., 41, 803, 2000.
87. Meurer-Grob, P., Kasparian, J., and Wade, R.H., Microtubule structure at improved resolution, Biochemistry, 40, 8000, 2001.
88. Wartmann, M. et al., Epothilones A and B accumulate several hundred fold inside cells, Proc. Am. Assoc. Cancer Res. 41, 213, 2000, Abstr. No. 1362.
89. Gupta, M.L. et al., Understanding tubulin-Taxol interactions: mutations that impart Taxol binding to yeast tubulin, Proc. Natl. Acad. Sci. USA, 100, 6394, 2003.
90. Bode, C.J. et al., Epothilone and paclitaxel: Unexpected differences in promoting the assembly and stabilisation of yeast microtubules, Biochemistry, 41, 3870, 2002.
91. Giannakakou, P. et al., A common pharmacophore for epothilone and taxanes: molecular basis for drug resistance conferred by tubulin mutations in human cancer cells, Proc. Natl. Acad. Sci. USA, 97, 2904, 2000.
92. He, L., Huang Yang, C.-P., and Horwitz, S.B., Mutations in β-tubulin map to domains involved in regulation of microtubule stability in epothilone-resistant cell lines, Mol. Cancer Ther., 1, 3, 2001.
93. Giannakakou, P. et al., A β-tubulin mutation confers epothilone resistance in human cancer cells, Proc. Am. Assoc. Cancer Res., 40, 284, 1999, Abstr. No. 1885.
94. Verrills, N.M. et al., Microtubule alterations and mutations induced by desoxyepothilone B: implications for drug-target interactions, Chem. Biol., 10, 597, 2003.
95. Martello, L.A. et al., Elevated levels of microtubule destabilizing factors in a Taxol-resistant/dependent A549 cell line with an β-tubulin mutation, Cancer Res., 63, 1207, 2003.
96. Verdier-Pinard, P. et al., Direct analysis of tubulin expression in cancer cell lines by electrospray ionization mass spectrometry, Biochemistry, 42, 12019, 2003.
97. Poruchynsky, M.S. et al., Accompanying protein alterations in malignant cells with a microtubulepolymerizing drug-resistance phenotype and a primary resistance mechanism, Biochem. Pharmacol., 62, 1469, 2001.
98. Khabele, D. et al., Tumor necrosis factor-α related gene response to epothilone B in ovarian cancer, Gynecol. Oncol., 93, 19, 2004.
99. Atadja, P. et al., Gene expression profiling of epothilone A–resistant cells, in Mechanisms of Drug Resistance in Epilepsy: Lessons from Oncology, Novartis Foundation Symposium, 2002, pp. 119-136.
100. Ioffe, M. et al., Epothilone induced cytotoxicity is dependent on p53 in prostate cells, Proc. Am. Assoc. Cancer Res., 44, Abstr. No. 829, 2003.
101. Uyar, D. et al., Apoptotic pathways of epothilone BMS 310705, Gynecol. Oncol., 91, 173, 2003.
102. Griffin, D. et al., Molecular determinants of epothilone B derivative (BMS 247550) and Apo-2L/TRAIL-induced apoptosis of human ovarian cancer cells, Gynecol. Oncol., 89, 37, 2003.
103. Yamaguchi, H. et al., Epothilone B analog (BMS-247550)-mediated cytotoxicity through induction of bax conformational change in human breast cancer cells, Cancer Res., 62, 466, 2002.
104. Bröker, L.E. et al., Late activation of apoptotic pathways plays a negligible role in mediating the cytotoxic effects of discodermolide and epothilone B in non-small cell lung cancer cells, Cancer Res., 62, 4081, 2002.
105. Pietras, K. et al., STI571 enhances the therapeutic index of epothilone B by a tumor-selective increase of drug uptake, Clin. Cancer Res., 9, 3779, 2003.
106. Wittmann, S. et al., Flavopiridol down-regulates antiapoptotic proteins and sensitizes human breast cancer cells to epothilone B-induced apoptosis, Cancer Res., 63, 93, 2003.
107. Moasser, M.M. et al., Farnesyl transferase inhibitors cause enhanced mitotic sensitivity to Taxol and epothilones, Proc. Natl. Acad. Sci. USA, 95, 1369, 1998.
108. Zhou, Y. et al., KDS-862 (epothilone D) with 5-fluorouracil in human colon cancer cell lines: synergistic antitumor effects, Proc. Am. Assoc. Cancer Res., 44, Abstr. No. 2746, 2003.
109. Fuino, I. et al., Histone deacetylase inhibitor IAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B, Mol. Cancer Ther., 2, 971, 2003.
110. Kim, J.-C. et al., Potential radiation-sensitizing effect of semisynthetic epothilone B in human lung cancer cells, Radiother. Oncol., 68, 305, 2003.
111. Martin, H.J., Drescher, M., and Mulzer, J., How stable are epoxides? A novel synthesis of epothilone B, Angew. Chem. Int. Ed., 39, 581, 2000.
112. Martin, H.J. et al., The 12,13-diol cyclization approach for a truly stereocontrolled total synthesis of epothilone B and the synthesis of a conformationally restrained analog, Chem. Eur. J., 7, 2261, 2001.
113. Mulzer, J., Karig, G., and Pojarliev, P., A novel highly stereoselective total synthesis of epothilone B and of its (12R, 13R) acetonide, Tetrahedron Lett., 41, 7635, 2000.
114. Meng, D. et al., Studies toward a synthesis of epothilone A: use of hydropyran templates for the management of acyclic stereochemical relationships, J. Org. Chem., 61, 7998, 1996.
115. Meng, D. et al., Total syntheses of epothilones A and B, J. Am. Chem. Soc., 119, 10073, 1997.
116. Schinzer, D. et al., Total synthesis of (–)-epothilone A, Angew. Chem. Int. Ed., 36, 523, 1997.
117. Nicolaou, K.C. et al., The olefin metathesis approach to epothilone A and its analogues, J. Am. Chem. Soc., 119, 7960, 1997.
118. Meng, D. et al., Remote effects in macrolide formation through ring-forming olefin metathesis: an application to the synthesis of fully active epothilone congeners, J. Am. Chem. Soc., 119, 2733, 1997.
119. Fürstner, A., Mathes, C., and Grela, K., Concise total syntheses of epothilone A and C based on alkyne metathesis, Chem. Commun., 1057, 2001.
120. Nicolaou, K.C. et al., Total syntheses of epothilones A and B via a macrolactonization-based strategy, J. Am. Chem. Soc., 119, 7974, 1997.
121. Balog, A. et al., Total synthesis of (–)-epothilone A, Angew. Chem. Int. Ed., 35, 2801, 1996.
122. Yang, Z. et al., Total synthesis of epothilone A: the olefin metathesis approach, Angew. Chem. Int. Ed., 36, 166, 1997.
123. Taylor, R.E. and Chen, Y. Total synthesis of epothilones B and D, Org. Lett., 3, 2221, 2001.
124. Liu, Z.-Y., Yu, C.-Z., Yang, J.-D., Chiral synthesis of the C3-13 segment of epothilone A, Synlett, 12, 1383, 1997.
125. Schinzer, D., Bauer, A., and Schieber, J., Synthesis of epothilones: stereoselective routes to epothilone B, Synlett, 8, 861, 1998.
126. Njardson, J.T., Biswas, K., and Danishefsky, S.J., Application of hitherto unexplored macrocyclization strategies in the epothilone series: novel epothilone analogs by total synthesis, Chem. Commun., 2759, 2002.
127. Bode, J.W. and Carreira, E.M., Stereoselective syntheses of epothilones A and B in nitrile oxide cycloadditions and related studies, J. Org. Chem., 66, 6410, 2001.
128. Bode, J. W. and Carreira, E.M., Epothilone B, J. Am. Chem. Soc., 123, 3611, 2001.
129. Biswas, K. et al., Highly concise routes to epothilones: the total synthesis and evaluation of epothilone 490, J. Am. Chem. Soc., 124, 9825, 2002.
130. Yamamoto, K. et al., Effects of temperature and concentration in some ring closing metathesis reactions, Tetrahedron Lett., 44, 3297, 2003.
131. White, J.D. et al., Total synthesis of epothilone B, epothilone D, and cis-and trans-9,10-dehydroepothilone D, J. Am. Chem. Soc., 123, 5407, 2001.
132. Sawada, D., Kanai, M., and Shibasaki, M., Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis, J. Am. Chem. Soc., 122, 10521, 2000.
133. Mulzer, J., Mantoulidis, A., and Öhler, E., Easy access to the epothilone family — synthesis of epothilone B, Tetrahedron Lett., 39, 8633, 1998.
134. Nicolaou, K.C. et al., Total synthesis of epothilone E and analogs with modified side chains through the Stille Coupling Reaction, Angew. Chem. Int. Ed., 37, 84, 1998.
135. Bertinato, P. et al., Studies toward a synthesis of epothilone A: stereocontrolled assembly of the acyl region and models for macrocyclization, J. Org. Chem., 61, 8000, 1996.
136. Rivkin, A. et al., Complex target-oriented total synthesis in the drug discovery process: the discovery of a highly promising family of second generation epothilones, J. Am. Chem. Soc., 125, 2899, 2003;
137. Sun, J. and Sinha S.C., Stereoselective total synthesis of epothilones by the metathesis approach involving C9-C10 bond formation, Angew. Chem. Int. Ed., 41, 1381, 2002.
138. May, S.A. and Grieco, P.A., Total synthesis of ()-epothilone B, Chem. Commun., 1597, 1998.
139. Mulzer, J. and Mantoulidis, A., Synthesis of the C(1)-C(9) segment of the cytotoxic macrolides epothilon A and B, Tetrahedron Lett., 37, 9179, 1996.
140. Schinzer, D., Limberg, A., and Böhm, O.M., Studies towards the total synthesis of epothilones: asymmetric synthesis of the key fragments, Chem. Eur. J., 2, 1477, 1996.
141. Nicolaou, K.C. et al., Total synthesis of epothilone E and related side-chain modified analogs via a Stille Coupling based strategy, Bioorg. Med. Chem., 7, 665, 1999;
142. Nicolaou, K.C. et al., Chemical synthesis and biological properties of pyridine epothilones. Chem. Biol., 7, 593, 2000.
143. Nicolaou, K.C. et al., Chemical synthesis and biological evaluation of novel epothilone B and trans-12,13-cyclopropyl epothilone B analogs, Tetrahedron, 58, 6413, 2002.
144. Nicolaou, K.C. et al., Synthesis and biological evaluation of 12,13-cyclopropyl and 12,13-cyclobutyl epothilones, Chem. Bio. Chem., 1, 69, 2001.
145. 6 subunit of epothilone, Tetrahedron Lett., 45, 1011, 2004.
146. Gabriel, T. and Wessjohann, L., The chromium-reformatsky reaction: asymmetric synthesis of the aldol fragment of the cytotoxic epothilons from 3-(2-bromoacyl)-2-oxazolidinones, Tetrahedron Lett., 38, 1363, 1997.
147. 6 segment of the epothilones, Tetrahedron, 56, 7859, 2000.
148. Stachel, S.J. and Danishefsky, S.J., Chemo-and stereoselective epoxidation of 12,13-desoxyepothilone B using 2,2-dimethyldioxirane, Tetrahedron Lett., 42, 6785, 2001.
149. Liu, Z.-Y. et al., Total synthesis of epothilone A through stereospecific epoxidation of the p-methoxybenzyl ether of epothilone C, Chem. Eur. J., 8, 3747, 2002.
150. Balog, A. et al., Stereoselective syntheses and evaluation of compounds in the 8-desmethylepothilone A. Series: some surprising observations regarding their chemical and biological properties, Tetrahedron Lett., 38, 4529, 1997.
151. Nicolaou, K.C. et al., Synthesis of 16-desmethylepothilone B: improved methodology for the rapid, highly selective and convergent construction of epothilone B and analogs, Chem. Commun., 519, 1999.
152. Nicolaou, K.C. et al., Total synthesis of 16-desmethylepothilone B, epothilone B10, epothilone F, and related side chain modified epothilone B analogs, Chem. Eur. J., 6, 2783, 2000.
153. Taylor, R.E. et al, Conformation–activity relationships in polyketide natural products. Towards the biologically active conformation of epothilone, Org. Biomol. Chem., 2, 127, 2004.
154. Taylor, R.E., Chen, Y., and Beatty, A., Conformation–activity relationships in polyketie natural products: a new perspective on the rational design of epothilone analogs, J. Am. Chem. Soc., 125, 26, 2003.
155. Nicolaou, K.C. et al, Total synthesis of 26-hydroxyepothilone B and related analogs, Chem. Commun., 2343, 1997.
156. Nicolaou, K.C. et al., Total synthesis of 26-hydroxy-epothilone B and related analogs via a macrolactonization based strategy, Tetrahedron, 54, 7127, 1998.
157. Chappell, M.D. et al., Probing the SAR of dEpoB via chemical synthesis: a total synthesis evaluation of C26-(1,3-dioxolanyl)-12,13-desoxyepothilone B, J. Org. Chem., 67, 7730, 2002.
158. Koch, G., Loiseleur, O., and Altmann, K.-H., Total synthesis of 26-fluoro-epothilone B, Synlett, 4, 693, 2004.
159. Chou, T.-C. et al., Design and total synthesis of a superior family of epothilone analogs, which eliminate xenograft tumors to a nonrelapsable state, Angew. Chem. Int. Ed., 42, 4762, 2003.
160. Altmann, K.-H. et al., Synthesis and biological evaluation of highly potent analogs of epothilones B and D, Bioorg. Med. Chem. Lett., 10, 2765, 2000.
161. Buey, R.M. et al., Interaction of epothilone analogs with the paclitaxel binding site: relationship between binding affinity, microtubule stabilisation, and cytotoxicity, Chem. Biol., 11, 225, 2004.
162. Johnson, J. et al., Synthesis, structure proof, and biological activity of epothilone cyclopropanes, Org. Lett., 2, 1537, 2000.
163. Nicolaou, K.C. et al., Chemical synthesis and biological evaluation of cis-and trans-12,13-cyclopropyl and 12,13-cyclobutyl epothilones and related pyridine side chain analogs, J. Am. Chem. Soc., 123, 9313, 2001.
164. Nicolaou, K.C. et al., Design, synthesis, and biological properties of highly potent epothilone B analogs, Angew. Chem. Int. Ed., 42, 3515, 2003.
165. Regueiro-Ren, A. et al., Synthesis and biological activity of novel epothilone aziridines, Org. Lett., 3, 2693, 2001.
166. Altmann, K.-H. et al., The total synthesis and biological assessment of trans-epothilone A, Helvetica Chim. Acta, 85, 4086, 2002.
167. Nicolaou, K.C. et al., Synthesis of epothilone A and B in solid and solution phase, Nature, 387, 268, 1997.
168. Glunz, P.W. et al., The synthesis and evaluation of 12,13-benzodesoxyepothilone B: a highly convergent route, Tetrahedron Lett., 40, 6895, 1999.
169. End, N. et al., Synthetic epothilone analogs with modifications in the northern hemispere and the heterocyclic side-chain-synthesis and biological evaluation, Fourth International Electronic Conference on Synthetic Organic Chemistry (ECSOC-4), September 1–30, 2000.
170. Quintard, D. et al., Enantioselective synthesis of 2,3-dehydro-3-desoxy-10-oxa epothilone D, Synlett, 13, 2033, 203.
171. Rivkin, A. et al., On the introduction of a trifluoromethyl substituent in the epothilone setting: chemical issues related to ring forming olefin metathesis and earliest biological findings, Org. Lett., 4, 4081, 2002.
172. Yoshimura, F. et al., Synthesis and conformational analysis of (E)-9,10-dehydroepothilone B: a suggestive link between the chemistry and biology of epothilones, Angew. Chem. Int. Ed., 42, 2518, 2003.
173. White, J.D. and Sundermann, K.F., Synthesis, conformational analysis, and bioassay of 9,10-didehydroepothilone D, Org. Lett., 4, 995, 2002.
174. Zhang, H.S., Zhong, C.F., and Bao, X.P., Studies of the total synthesis of epothilone B and D: a facile synthesis of C7-C14 and C15-C21 fragments, Chinese Chem. Lett., 14, 115, 2003.
175. 3-carene, Russ. J. Org. Chem., 39, 75, 2003.
176. Akbutina, F.A. et al., Chiral synthetic block based on (R)-pantolactone, Mendeleev Commun., 151, 2003.
177. Ermolenko, M.S. and Potier, P., Synthesis of epothilones B and D from D-glucose, Tetrahedron Lett., 43, 2895, 2002.
178. Machajewski, T.D. and Wong, C.-H., Chemoenzymatic synthesis of Key epothilone fragments, Synthesis, 1469, 1999.
179. Shioji, K. et al., Synthesis of C1-C6 fragment for epothilone A via lipase-catalyzed optical resolution, Synth. Comm., 31, 3569, 2001.
180. Bornscheuer, U.T., Altenbuchner, J., and Meyer, H.H., Directed evolution of an esterase for the stereoselective resolution of a key intermediate in the synthesis of epothilones, Biotechnol. Bioeng., 58, 554, 1998.
181. Sinha, S.C. et al., Synthesis of epothilone analogs by antibody-catalyzed resolution of thiazole aldol synthons on a multigram scale. Biological consequences of C-13 alkylation of epothilones, Chem. Bio. Chem, 2, 656, 2001.
182. Sinha, S.C. et al., Sets of aldolase antibodies with antipodal reactivities. Formal synthesis of epothilone E by large-scale antibody-catalyzed resolution of thiazole aldol, Org. Lett., 1, 1623, 1999.
183. Sinha, S.C., Barbas III C.F., and Lerner, R.A., The antibody catalysis route to the total synthesis of epothilones, Proc. Natl. Acad. Sci. USA, 95, 14603, 1998.
184. Liu, J. and Wong, C.-H., Aldolase-catalyzed asymmetric synthesis of novel pyranose synthons as a new entry to heterocycles and epothilones, Angew. Chem. Int. Ed., 41, 1404, 2002.
185. Nicolaou, K.C. et al., Designed epothilones: combinatorial synthesis, tubulin assembly properties, and cytotoxic action against Taxol-resistant tumor cells, Angew. Chem. Int. Ed., 36, 2097, 1997.
186. Storer, R.J. et al., A total synthesis of epothilones using solid-supported reagents and scavengers, Angew. Chem. Int. Ed., 42, 2521, 2003;
187. Storer, R.I. et al., Multi-step application of immobilized reagents and scavengers: a total synthesis of epothilone C, Chem. Eur. J., 10, 2529, 2004.
188. Sefkow, M. et al., Oxidative and reductive transformations of epothilone A, Bioorg. Med. Chem. Lett., 8, 3025, 1998.
189. Sefkow, M., Kiffe, M., and Höfle, G., Derivatization of the C12-C13 functional groups of epothilones A, B and C, Bioorg. Med. Chem. Lett., 8, 3031, 1998.
190. Höfle, G. et al., Epothilone A–D and their thiazole-modified analogs as novel anticancer agents, Pure Appl. Chem., 71, 2019, 1999.
191. Boddy, C.N. et al., Epothilone C macrolactonization and hydrolysis are catalyzed by the isolated thioesterase domain of epothilone polyketide synthase, J. Am. Chem. Soc., 125, 3428, 2003.
192. Regueiro-Ren, A. et al., SAR and pH stability of cyano-substituted epothilones, Org. Lett., 4, 3815, 2002.
193. Vite, G.D. et al., (BMS), US Patent, 6399638 B1 (June, 4, 2002).
194. Dong, S.D. et al., Rapid access to epothilone analogs via semisynthetic degradation and reconstruction of epothilone D, Tetrahedron Lett., 45, 1945, 2004.
195. Karama, U. and Höfle, G., Synthesis of epothilone 16,17-alkyne by replacement of the C13-C15(O)-ring segment of natural epothilone C, Eur. J. Org. Chem., 1042, 2003.
196. Sefkow, M. and Höfle, G., Substitutions at the thiazole moiety of epothilone, Heterocyles, 48, 2485, 1998.
197. Glaser, N., Doctoral Thesis, Technical University of Braunschweig, 2001.
198. Matson, J.A. et al., (BMS), International Patent Application, WO 00/39276 (July 6, 2000).
199. Hamel, E., Evaluation of antimitotic agents by quantitative comparisons of their effects on the polymerization of purified tubulin, Cell Biochem. Biophys., 38, 1, 2003.
200. Nicolaou, K.C. et al., Variation der Ringgröße von Epothilonen — Totalsynthese von [14]-, [15], [17]-und [18]Epothilon A, Angew. Chem., 110, 85, 1998;
201. Rivkin, A. et al., Total syntheses of [17]-and [18]dehydrodesoxyepothilones B via a concise ring-closing metathesis-based strategy: correlation of ring size with biological activity in the epothilone series, J. Org. Chem., 67, 7737, 2002.
202. U.S. Patent Application Serial No. 09/280,210, U.S. Patent No. 6,498,257 B1, 2002.
203. Nicolaou, K.C. et al., Synthesis and biological properties of C12,13-cyclopropyl-epothilone A and related epothilones, Chem. Biol., 5, 365, 1998.
204. Su, D.-S. et al., Total synthesis of (-)-epothilone B: an extension of the Suzuki coupling method and insights into structure-activity relationships of the epothilones, Angew. Chem. Int. Ed., 36, 757, 1997.
205. Ganesh, T. et al., Synthesis and biological evaluation of fluorescently labeled epothilone analogs for tubulin binding studies, Tetrahedron, 59, 9979, 2003.
206. Stachel, S. J. et al., On the total synthesis and preliminary biological evaluations of 15(R) and 15(S) Aza-dEpoB: a Mitsunobu inversion at C15 in pre-epothilone fragments, Org. Lett., 2, 1637, 2000.
207. Victory, S.F. et al., Relative stereochemistry and solution conformation of the novel paclitaxel-like antimitotic agent epothilone A, Bioorg. Med. Chem. Lett., 6, 893, 1996.
208. Taylor, R.E. and Zajicek, J., Conformational properties of epothilone, J. Org. Chem., 64, 7224, 1999;
209. Taylor, R.E. and Zajicek, J., Conformational properties of epothilone, J. Org. Chem. 65, 5449, 2000.
210. Carlomagno, T. et al., The high-resolution solution structure of epothilone A bound to tubulin: an understanding of the structure-activity relationships for a powerful class of antitumor agents, Angew. Chem. Int. Ed., 42, 2511, 2003.
211. Carlomagno, T. et al., Derivation of dihedral angles from CH-CH dipolar-dipolar cross-correlated relaxation rates: a C-C torsion involving a quaternary carbon atom in epothilone A bound to tubulin, Angew. Chem. Int. Ed., 42, 2515, 2003.
212. The spectral data for the supposed epothilone/tubulin complex in aqueous buffer are compared with that of epothilone in dichloromethane, and the tubulin is stated not to polymerise even in the presence of a 100 fold molar excess of epothilone.
213. Ojima, I. et al., A common pharmacophore for cytotoxic natural products that stabilize microtubules, Proc. Natl. Acad. Sci. USA, 96, 4256, 1999.
214. Wang, M. et al., A unified and quantitative receptor model for the microtubule binding of paclitaxel and epothilone, Org. Lett., 1, 43, 1999.
215. He, L. et al., A common pharmacophore for Taxol and the epothilones based on the biological activity of a taxane molecule lacking a C13 side chain, Biochemistry, 39, 3972, 2000.
216. Wartmann, M., Preclinical pharmacological profile of ABJ879, a novel epothilone B analog with potent and protracted anti-tumor activity, AACR Ann. Meet. Orlando, March 27–31, 2004, Abstr. No. 5440.
217. DiLea, C. et al., A PK-PD dose optimization strategy for the microtubule stabilizing agent ABJ879, AACR Ann. Meet. Orlando, March 27–31, 2004, Abstr. No. 5132.
218. Johnson et al., Oral bioavailability of KOS-862 (epothilone D), a potent stabilizer of microtubulin polymerization in rats and Beagle dogs. Proc. Am. Assoc. Cancer Res., 44, Abstr. No. 5339, 2003.
219. Rosen, P.J. et al., KOS-862 (epothilone D): results of a phase I dose-escalating trial in patients with advanced malignancies, Proc. Am. Soc. Clin. Oncol. 21: Abstr. No. 413, 2002.
220. Bocci, G., Nicolaou, K.C., and Kerbel, R.S., Protracted low-dose effects on human endothelial cell proliferation and survival in vitro reveal a selective antiangiogenic window for various chemotherapeutic drugs, Cancer Res., 62, 6938, 2002.
221. Blum, W. et al., In vivo metabolism of epothilone B in tumor-bearing nude mice: identification of three new epothilone B metabolites by capillary high-pressure liquid chromatography/mass spectrometry/tandem mass spectrometry, Rapid Commun. Mass Spectrom., 15, 41, 2001.
222. Altaha, R. et al., Epothilones: a novel class of non-taxane microtubule-stabilizing agents, Curr. Pharm. Design, 8, 1707, 2002.
223. McDaid, H.M. et al., Validation of the pharmacodynamics of BMS-247550, an analog of epothilone B, during a phase I clinical study, Clin. Cancer Res., 8, 2035, 2002.
224. Borman, S., First disclosures of clinical candidates, Chem. Eng. News, 80, 35, 2002.
225. Rothermel, J. et al., EPO906 (epothilone B): A promising novel microtubule stabilizer, Sem. Oncol., 30, Suppl. 6, 51, 2003.
226. Agrawal, M. et al., Treatment of recurrent cervical adenocarcinoma with BMS-247550, an epothilone B analog, Gynecol. Oncol., 90, 96, 2003.
227. Abraham, J. et al., Phase I trial and pharmacokinetic study of BMS-247550, an epothilone B analog, administered intravenously on a daily schedule for five days, J. Clin. Oncol., 21, 1866, 2003.
228. Smaletz, O. et al., Pilot study of epothilone B analog (BMS-247550) and estramustine phosphate in patients with progressive metastatic prostate cancer following castration, Ann. Oncol., 14, 1518, 2003.
229. Nettles, J.H. et al., The Binding Mode of Epothilone A on α,β-Tubulin by Electron Crystallography, Science, 305, 866, 2004.
230. Heinz, D.H. et al., Much Anticipated — The Bioactive Conformation of Epothilone and Its Binding to Tubulin, Angew. Chem. Int. Ed., 44, 1298, 2005.