Chemistry and Biology of Epothilones

Natural Products in Medicinal Chemistry

Volumn , Issue , 2014, Pages 81-126

  Altmann, Karl Heinz ^a   Schinzer, Dieter ^b  

^a ETH ZURICH   (Switzerland)

^b OTTO VON GUERICKE UNIVERSITY   (Germany)

Author keywords

Cancer; Drug discovery; Epothilones; Microtubules; Polyketide macrocycles; Total synthesis

Indexed keywords

EID: 84926467435     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1002/9783527676545.ch03     Document Type: Chapter

References (162)

1. Dumontet, C. and Jordan, M.A. (2010) Microtubule-binding agents: a dynamic field of cancer therapeutics. Nature Reviews. Drug Discovery, 9, 790-803.
2. Jordan, M.A. and Wilson, L. (2004) Microtubules as a target for anticancer drugs. Nature Reviews. Cancer, 4, 253-265.
3. Rowinsky, E.K. (1997) The development and clinical utility of the taxane class of antimicrotubule chemotherapy agents. Annual Review of Medicine, 48, 353-374.
4. Agarwal, N., Sonpavde, G., and Sartor, O. (2011) Cabazitaxel for the treatment of castration-resistant prostate cancer. Future Oncology, 7, 15-24.
5. Chen, S.-M., Meng, L.-H., and Ding, J. (2010) New microtubule-inhibiting anticancer agents. Expert Opinion on Investigational Drugs, 19, 329-343.
6. www.cancer.gov/cancertopics/druginfo/fda-eribulinmesylate.
7. Schiff, P.B., Fant, J., and Horwitz, S.B. (1979) Promotion of microtubule assembly in vitro by taxol. Nature, 277, 665-667.
8. Höfle, G. and Reichenbach, H. (2005) Epothilone, a myxobacterial metabolite with promising antitumor activity, in Anticancer Agents from Natural Products (eds G.M. Cragg, D.G.I. Kingston, and D.J. Newman), Taylor & Francis, Boca Raton, FL, pp. 413-450.
9. Gerth, K., Bedorf, N., Höfle, G., Irschik, H., and Reichenbach, H. (1996) Epothilons A and B: antifungal and cytotoxic compounds from Sorangium cellulosum (Myxobacteria). Production physico-chemical and biological properties. The Journal of Antibiotics, 49, 560-563 (see also Höfle, G., Bedorf, N., Gerth, K., Reichenbach, H., German Patent Disclosure, DE 4138042, 1993; Chemical Abstracts 120, 52841 (1993)).
10. Hardt, I.H., Steinmetz, H., Gerth, K., Sasse, F., Reichenbach, H., and Höfle, G. (2001) New natural epothilones from Sorangium cellulosum strains So ce90/B2 and So ce90/D13: isolation structure elucidation and SAR studies. Journal of Natural Products, 64, 847-856.
11. Bollag, D.M., McQueney, P.A., Zhu, J., Hensens, O., Koupal, L., Liesch, J., Goetz, M., Lazarides, E., and Woods, C.M. (1995) Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action. Cancer Research, 55, 2325-2333.
12. Altmann, K.-H. (2001) Microtubule-stabilizing agents: a growing class of important anticancer drugs. Current Opinion in Chemical Biology, 5, 424-432.
13. Myles, D.C. (2002) Emerging microtubule stabilizing agents for cancer chemotherapy. Annual Reports in Medicinal Chemistry, 37, 125-132.
14. Altmann, K.-H. and Gertsch, J. (2007) Anticancer drugs from nature: natural products as a unique source of new microtubule-stabilizing agents. Natural Product Reports, 24, 327.
15. Miller, J.H., Singh, A.J., and Northcote, P.T. (2010) Microtubule-stabilizing drugs from marine sponges: focus on peloruside A and zampanolide. Marine Drugs, 8, 1059-1079.
16. Field, J.J., Singh, A.J., Kanakkanthara, A., Halafihi, T., Northcote, P.T., and Miller, J. (2009) Microtubule-stabilizing activity of zampanolide, a potent macrolide isolated from the Tongan marine sponge Cacospongia mycofijiensis. Journal of Medicinal Chemistry, 52, 7328.
17. Borzilleri, R.M. and Vite, G.D. (2003) Epothilones: new tubulin polymerization agents in preclinical and clinical development. Drugs of the Future, 27, 1149.
18. Wartmann, M. and Altmann, K.-H. (2002) The biology and medicinal chemistry of epothilones. Current Medicinal Chemistry Anticancer Agents, 2, 123.
19. Altmann, K.-H. (2003) Epothilone B and its analogs: a new family of anticancer agents. Mini Reviews in Medicinal Chemistry, 3, 149.
20. Altmann, K.-H. (2005) Recent developments in the chemistry and biology of epothilones. Current Pharmaceutical Design, 11, 1595-1613.
21. Altmann, K.-H., Pfeiffer, B., Arseniyadis, S., Pratt, B.A., and Nicolaou, K.C. (2007) The chemistry and biology of epothilones: the wheel keeps turning. ChemMedChem, 2, 397-423.
22. Altmann, K-.H., Höfle, G., Müller, R., Mulzer, J., Prantz, K. (2009), in The Epothilones: An Outstanding Family of Anti-Tumor Agents, vol. 90 (eds A.D. Kinghorn, H. Falk, and J. Kobayashi), Springer.
23. Kowalski, R.J., Giannakakou, P., and Hamel, E. (1997) Activities of the microtubule-stabilizing agents epothilones A and B with purified tubulin and in cells resistant to paclitaxel (Taxol). The Journal of Biological Chemistry, 272, 2534-2541.
24. Nettles, J.H., Li, H.L., Cornett, B., Krahn, J.M., Snyder, J.P., and Downing, K.H. (2004) The binding mode of epothilone A on a,b-tubulin by electron crystallography. Science, 305, 866-869.
25. K-.H., Altmann, M., Wartmann, T. O'Reilly (2000) Epothilones and related structures: a new class of microtubule inhibitors with potent in vivo antitumor activity. Biochimica et Biophysica Acta, 1470, M79-M81.
26. Giannakakou, P., Sackett, D.L., Kang, Y.K., Zhan, Z.R., Buters, J.T.M., Fojo, T., and Poruchynsky, M.S. (1997) Paclitaxel-resistant human ovarian cancer cells have mutant b-tubulins that exhibit impaired paclitaxel-driven polymerization. The Journal of Biological Chemistry, 272, 17118-17125.
27. Lee, S.H., Son, S.M., Son, D.J., Kim, S.M., Kim, T., Song, S., Moon, D.C., Lee, H.W., Ryu, J.C., Yoon, D.-Y., and Hong, J.T. (2007) Epothilones induce human colon cancer SW620 cell apoptosis via the tubulin polymerization-independent activation of the nuclear factor-kB/IkB kinase signal pathway. Molecular Cancer Therapeutics, 6, 2786-2797.
28. Giannakakou, P., Gussio, R., Nogales, E., Downing, K.H., Zaharevitz, D., Bollbuck, B., Poy, G., Sackett, D., Nicolaou, K.C., and Fojo, T. (2000) A common pharmacophore for epothilone and taxanes: molecular basis for drug resistance conferred by tubulin mutations in human cancer cells. Proceedings of the National Academy of Sciences of the United States of America, 97, 2904-2909.
29. He, L., Yang, C.-P., and Horwitz, S.B. (2001) Mutations in beta-tubulin map to domains involved in regulation of microtubule stability in epothilone-resistant cell lines. Molecular Cancer Therapeutics, 1, 3-10.
30. Hopper-Borge, E., Xu, X., Shen, T., Shi, Z., Chen, Z.S., and Kruh, G.D. (2009) Human multidrug resistance protein 7 (ABCC10) is a resistance factor for nucleoside analogues and epothilone B. Cancer Research, 69, 178-184.
31. O'Reilly, T., Wartmann, M., Brueggen, J., Allegrini, P.R., Flörsheimer, A., Maira, M., and McSheehy, P.M.J. (2008) Pharmacokinetic profile of the microtubule stabilizer patupilone in tumor-bearing rodents and comparison of anti-cancer activity with other MTS in vitro and in vivo. Cancer Chemotherapy and Pharmacology, 62, 1045-1054.
32. O'Reilly, T., McSheehy, P.M.J., Wenger, F., Hattenberger, M., Muller, M., Vaxelaire, J., Altmann, K.-H., and Wartmann, M. (2005) EPO906 (epothilone B) is active in vivo against experimental prostate tumors. The Prostate, 65, 231-240.
33. Rothermel, J., Wartmann, M., Chen, T.L., and Hohneker, J. (2003) EPO906 (epothilone B): a promising novel microtubule stabilizer. Seminars in Oncology, 30, 51-55.
34. Borzilleri, R.M., Zheng, X.P., Schmidt, R.J., Johnson, J.A., Kim, S.H., DiMarco, J.D., Fairchild, C.R., Gougoutas, J.Z., Lee, F.Y.F., Long, B.H., and Vite, G.D. (2000) A novel application of a Pd(0)-catalyzed nucleophilic substitution reaction to the regio- and stereoselective synthesis of lactam analogues of the epothilone natural products. Journal of the American Chemical Society, 122, 8890-8897.
35. Rubin, E.H., Rothermel, J., Tesfaye, F., Chen, T., Hubert, M., Ho, Y.Y., Hsu, C.H., and Oza, A.M. (2005) Phase I dose-finding study of weekly single-agent patupilone in patients with advanced solid tumors. Journal of Clinical Oncology, 23, 9120-9129.
36. Zhang, P., Sun, M., Qiu, R., Tang, L., Dou, G., and Xu, B. (2011) Phase I clinical and pharmacokinetic study of UTD1, a genetically engineered epothilone analog in patients with advanced solid tumors. Cancer Chemotherapy and Pharmacology, 68, 971-978.
37. Vlahov, I.R., Vite, G.D., Kleindl, P.J., Wang, Y., Santhapuram, H.K.R., You, F., Howard, S.J., Kim, S.-H., Lee, F.F.Y., and Leamon, C.P. (2010) Regioselective synthesis of folate receptor-targeted agents derived from epothilone analogs and folic acid. Bioorganic & Medicinal Chemistry Letters, 20, 4578-4581.
38. Lechleider, R.J., Kaminskas, E., Jiang, X., Aziz, R., Bullock, J., Kasliwal, R., Harapanhalli, R., Pope, S., Sridhara, R., Leighton, J., Booth, B., Dagher, R., Justice, R., and Pazdur, R. (2008) Ixabepilone in combination with capecitabine and as monotherapy for treatment of advanced breast cancer refractory to previous chemotherapies. Clinical Cancer Research, 14, 4378-4384.
39. Bystricky, B. and Chau, I. (2011) Patupilone in cancer treatment. Expert Opinion on Investigational Drugs, 20, 107-117.
40. www.novartis.com/newsroom/media-releases/en/2010/1419057.shtml.
41. Wartmann, M., Loretan, J., Reuter, R., Hattenberger, M., Muller, M., Vaxelaire, J., Maira, S.-M., Flörsheimer, A., O'Reilly, T., Nicolaou, K.C., and Altmann, K.-H. (2004) Proceedings of the American Association for Cancer Research, 45, Abstract 5440 (the compound is no longer part of the (published) Novartis Oncology pipeline).
42. Höfle, G.H., Bedorf, N., Steinmetz, H., Schomburg, D., Gerth, K., and Reichenbach, H. (1996) Antibiotics from gliding bacteria. 77. Epothilone A and B: novel 16-membered macrolides with cytotoxic activity: isolation crystal structure and conformation in solution. Angewandte Chemie -International Edition in English, 35, 1567-1569.
43. Nicolaou, K.C., Roschangar, F., and Vourloumis, D. (1998) Chemical biology of epothilones. Angewandte Chemie -International Edition, 37, 2015-2045.
44. Harris, C.R. and Danishefsky, S.J. (1999) Complex target-oriented synthesis in the drug discovery process: a case history in the dEpoB series. The Journal of Organic Chemistry, 64, 8434-8456.
45. Mulzer, J., Martin, H.J., and Berger, M. (1999) Progress in the synthesis of chiral heterocyclic natural products: epothilone B and tartrolon B. Journal of Heterocyclic Chemistry, 36, 1421-1436.
46. Nicolaou, K.C., Ritzen, A., and Namoto, K. (2001) Recent developments in the chemistry biology and medicine of the epothilones. Chemical Communications, 1523-1535.
47. Altmann, K.-H. (2004) The merger of natural product synthesis and medicinal chemistry: on the chemistry and chemical biology of epothilones. Organic & Biomolecular Chemistry, 2, 2137-2152.
48. Watkins, E.B., Chittiboyina, A.C., Jung, J.C., and Avery, M.A. (2005) The epothilones and related analogues: a review of their syntheses and anti-cancer activities. Current Pharmaceutical Design, 11, 1615-1653.
49. Pfeiffer, B., Kuzniewski, C.N., Wullschleger, C., and Altmann, K.-H. (2009) Macrolide-based microtubule-stabilizing agents: chemistry and structure-activity relationships. Topics in Current Chemistry, 286, 1-72.
50. Klar, U., Buchmann, B., Schwede, W., Skuballa, W., Hoffmann, J., and Lichtner, R.B. (2006) Total synthesis and antitumor activity of ZK-EPO: the first fully synthetic epothilone in clinical development. Angewandte Chemie -International Edition, 45, 7942-7948.
51. Martin, H.J., Drescher, M., and Mulzer, J. (2000) How stable are epoxides? A novel synthesis of epothilone B. Angewandte Chemie -International Edition, 39, 581-583.
52. Sun, J. and Sinha, S.C. (2001) Stereoselective total synthesis of epothilones by the metathesis approach involving C9-C10 bond formation. Angewandte Chemie -International Edition, 41, 1381-1383.
53. Schinzer, D., Limberg, A., Bauer, A., Böhm, O.M., and Cordes, M. (1997) Total synthesis of (-)-epothilone A. Angewandte Chemie -International Edition in English, 36, 523-524.
54. Nicolaou, K.C., He, Y., Vourloumis, D., Vallberg, H., and Zang, Z. (1997) Total synthesis of epothilone A: the olefin metathesis approach. Angewandte Chemie -International Edition in English, 36, 166-168.
55. Balog, A., Meng, D., Kamenecka, T., Bertinato, P., Su, D.S., Sorensen, E.J., and Danishefsky, S.J. (1996) Total synthesis of (-)-epothilone A. Angewandte Chemie -International Edition in English, 35, 2801-2803.
56. Fürstner, A., Mathes, C., and Lehmann, C.W. (2001) Alkyne metathesis: development of a novel molybdenum-based catalyst system and its application to the total synthesis of epothilone A and C. Chemistry -A European Journal, 7, 5299-5317.
57. Yu, M., Wang, C., Kyle, A.F., Jakubec, P., Dixon, D.J., Schrock, R.R., and Hoveyda, A.M. (2011) Synthesis of macrocyclic natural products by catalyst-controlled stereoselective ring-closing metathesis. Nature, 479, 88-93.
58. Meng, D., Bertinato, P., Balog, A., Su, D.S., Kamenecka, T., Sorensen, E.J., and Danishefsky, S.J. (1997) Total syntheses of epothilones A and B. Journal of the American Chemical Society, 119, 10073-10092.
59. Martin, H.J., Pojarliev, P., Kahlig, H., and Mulzer, M. (2001) The 12,13-diol cyclization approach for a truly stereocontrolled total synthesis of epothilone B and the synthesis of a conformationally restrained analog. Chemistry -A European Journal, 7, 2261-2271.
60. Schinzer, D., Bauer, A., Böhm, M.O., Limberg, A., and Cordes, M. (1999) Total synthesis of (-)-epothilone A. Chemistry -A European Journal, 5, 2483-2491.
61. Nicolaou, K.C., Hepworth, D., Finlay, M.R.V., King, N.P., Werschkun, B., and Bigot, A. (1999) Synthesis of 16-desmethylepothilone B: improved methodology for the rapid highly selective and convergent construction of epothilone B and analogues. Chemical Communications, 519-520.
62. Frein, J.D., Taylor, R.E., and Sackett, D.L. (2009) New sources of chemical diversity inspired by biosynthesis: rational design of a potent epothilone analog. Organic Letters, 11, 3186-3189.
63. Nicolaou, K.C., He, Y., Vourloumis, D., Vallberg, H., Roschangar, F., Sarabia, F., Ninkovic, S., Yang, Z., and Trujillo, J.I. (1997) The olefin metathesis approach to epothilone A and its analogs. Journal of the American Chemical Society, 119, 7960-7973.
64. Nicolaou, K.C., Ninkovic, S., Sarabia, F., Vourloumis, D., He, Y., Vallberg, H., Finlay, M.R.V., and Yang, Z. (1997) Total syntheses of epothilones A and B via a macrolactonization-based strategy. Journal of the American Chemical Society, 119, 7974-7991.
65. Harris, C.R., Kuduk, S.D., Balog, A., Savin, K., Glunz, P., and Danishefsky, S.J. (1999) New chemical synthesis of the promising cancer chemotherapeutic agent 12,13-desoxyepothilone B: discovery of a surprising long-range effect on the diastereoselectivity of an aldol condensation. Journal of the American Chemical Society, 121, 7050-7062.
66. Zhu, B. and Panek, J.S. (2001) Methodology based on chiral silanes in the synthesis of polypropionate-derived natural products: total synthesis of epothilone A. European Journal of Organic Chemistry, 9, 1701-1714.
67. Stachel, S.J., Lee, C.B., Spassova, M., Chappell, M.D., Bornmann, W.G., Danishefsky, S.J., Chou, T.C., and Guan, Y.B. (2001) 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. The Journal of Organic Chemistry, 66, 4369-4378.
68. Schinzer, D., Altmann, K.-H., Stuhlmann, F., Bauer, A., and Wartmann, M. (2000) Synthesis and biological evaluation of aza-epothilones. ChemBioChem, 1, 67-70.
69. Johnson, J., Kim, S.H., Bifano, M., DiMarco, J., Fairchild, C., Gougoutas, J., Lee, F., Long, B., Tokarski, J., and Vite, G. (2000) Synthesis structure proof and biological activity of epothilone cyclopropanes. Organic Letters, 2, 1537-1540.
70. Regueiro-Ren, A., Leavitt, K., Kim, S.H., Höfle, G., Kiffe, M., Gougoutas, J.Z., DiMarco, J.D., Lee, F.Y.F., Fairchild, C.R., Long, B.H., and Vite, G.D. (2002) SAR and pH stability of cyano-substituted epothilones. Organic Letters, 4, 3815-3818.
71. Altmann, K.-H., Gaugaz, F.Z., and Schiess, R. (2011) Diversity through semisynthesis: the chemistry and biological activity of semisynthetic epothilone derivatives. Molecular Diversity, 15, 383-399.
72. Balog, A., Harris, C., Savin, K., Zhang, X.G., Chou, T.C., and Danishefsky, S.J. (1998) A novel aldol condensation with 2-methyl-4-pentenal and its application to an improved total synthesis of epothilone B. Angewandte Chemie -International Edition, 37, 2675-2678.
73. Su, D.-S., Meng, D., Bertinato, P., Balog, A., Sorensen, E.J., Danishefsky, S.J., Zheng, Y.-H., Chou, T.C., He, L., and Horwitz, S.B. (1997) Total synthesis of (-)-epothilone B: an extension of the Suzuki coupling method and insights into structure-activity relationships of the epothilones. Angewandte Chemie -International Edition in English, 35, 757-759.
74. Meng, D.F., Su, D.S., Balog, A., Bertinato, P., Sorensen, E.J., Danishefsky, S.J., Zheng, Y.H., Chou, T.C., He, L.F., and Horwitz, S.B. (1997) An application to the synthesis of fully active epothilone congeners. Journal of the American Chemical Society, 119, 2733-2734.
75. Su, D.S., Balog, A., Meng, D.F., Bertinato, P., Danishefsky, S.J., Zheng, Y.H., Chou, T.C., He, L.F., and Horwitz, S.B. (1997) Structure-activity relationships of the epothilones and the first in vivo comparison with paclitaxel. Angewandte Chemie -International Edition in English, 36, 2093-2096.
76. Nicolaou, K.C., Vourloumis, D., Li, T., Pastor, J., Winssinger, N., He, Y., Ninkovic, S., Sarabia, F., Vallberg, H., Roschangar, F., King, N.P., Finlay, M.R., Giannakakou, P., Verdier-Pinard, P., and Hamel, E. (1997) Designed epothilones: combinatorial synthesis tubulin assembly properties and cytotoxic action against taxol-resistant tumor cells. Angewandte Chemie -International Edition in English, 36, 2097-2103.
77. Nicolaou, K.C., Winssinger, N., Pastor, J., Ninkovic, S., Sarabia, F., He, Y., Vourloumis, D., Yang, Z., Li, T., Giannakakou, P., and Hamel, E. (1997) Synthesis of epothilones A and B in solid and solution phase. Nature, 387, 268-272.
78. Chou, T.C., Zhang, X.G., Balog, A., Su, D.S., Meng, D., Savin, K., Bertino, J.R., and Danishefsky, S.J. (1998) Desoxyepothilone B: an efficacious microtubule-targeted antitumor agent with a promising in vivo profile relative to epothilone B. Proceedings of the National Academy of Sciences of the United States of America, 95, 9642-9647.
79. Chou, T.-C., Zhang, X.G., Harris, C.R., Kuduk, S.D., Balog, A., Savin, K.A., Bertino, J.R., and Danishefsky, S.J. (1998) Desoxyepothilone B is curative against human tumor xenografts that are refractory to paclitaxel. Proceedings of the National Academy of Sciences of the United States of America, 95, 15798-15802.
80. Monk, J.P., Villalona-Calero, M., Larkin, J., Otterson, G., Spriggs, D.S., Hannah, A.L., Cropp, G.F., Johnson, R.G., and Hensley, M.L. (2012) A phase 1 study of KOS-862 (epothilone D) co-administered with carboplatin (paraplatin) in patients with advanced solid tumors. Investigational New Drugs, 30, 1676-1683.
81. Beer, T. M., Higano, C. S., Saleh, M., Dreicer, R., Hudes, G., Picus, J., Rarick, M., Fehrenbacher, L., Hannah, A. L. (2007) Phase II study of KOS-862 in patients with metastatic androgen independent prostate cancer previously treated with docetaxel. Investigational New Drugs, 25, 565-570.
82. Barten, D.M., Fanara, P., Andorfer, C., Hoque, N., Wong, P.Y.A., Husted, K.H., Cadelina, G.W., DeCarr, L.B., Yang, L., Liu, V., Fessler, C., Protassio, J., Riff, T., Turner, H., Janus, C.G., Sankaranarayanan, S., Polson, C., Meredith, J.E., Gray, G., Hanna, A., Olson, R.E., Kim, S.-H., Vite, G.D., Lee, F.Y., and Albright, C.F. (2012) Hyperdynamic microtubules cognitive deficits and pathology are improved in tau transgenic mice with low doses of the microtubule-stabilizing agent BMS-241027. The Journal of Neuroscience, 32, 7137.
83. Nicolaou, K.C., Namoto, K., Li, J., Ritzen, A., Ulven, T., Shoji, M., Zaharevitz, D., Gussio, R., Sackett, D.L., Ward, R.D., Hensler, A., Fojo, T., and Giannakakou, P. (2000) Synthesis and biological evaluation of 12,13-cyclopropyl and 12,13-cyclobutyl epothilones. ChemBioChem, 2, 69-75.
84. Nicolaou, K.C., Namoto, K., Ritzen, A., Ulven, T., Shoji, M., Li, J., D'Amico, G., Liotta, D., French, C.T., Wartmann, M., Altmann, K.-H., and Giannakakou, P. (2001) Chemical synthesis and biological evaluation of cis- and trans-12,13-cyclopropyl and 12,13-cyclobutyl epothilones and related pyridine side chain analogues. Journal of the American Chemical Society, 123, 9313-9323.
85. Buey, R.M., Díaz, J.F., Andreu, J.M., O'Brate, A., Giannakakou, P., Nicolaou, K.C., Sasmal, P.K., Ritzen, A., and Namoto, K. (2004) Interactions of epothilone analogs with the paclitaxel binding site: relationship between binding affinity microtubule stabilization and cytotoxicity. Chemistry & Biology, 11, 225-236.
86. Nicolaou, K.C., Ritzen, A., Namoto, K., Buey, R.M., Diaz, J.F., Andreu, J.M., Wartmann, M., Altmann, K.-H., O'Brate, A., and Giannakakou, P. (2002) Chemical synthesis and biological evaluation of novel epothilone B and trans-12,13-cyclopropyl epothilone B analogues. Tetrahedron, 58, 6413-6432.
87. Nicolaou, K.C., Sasmal, P.K., Rassias, G., Reddy, M.V., Altmann, K.-H., Wartmann, M., O'Brate, A., and Giannakakou, P. (2003) Design synthesis and biological properties of highly potent epothilone B analogues. Angewandte Chemie -International Edition, 42, 3515-3520.
88. Schiess, R., Gertsch, J., Schweizer, W.B., and Altmann, K.-H. (2011) Stereoselective synthesis of 12,13-cyclopropyl-epothilone B and side-chain-modified variants. Organic Letters, 13, 1436.
89. Altmann, K.-H., Blommers, M.J.J., Caravatti, G., Flörsheimer, A., Nicolaou, K.C., O'Reilly, T., Schmidt, A., Schinzer, D., and Wartmann, M. (2001) Synthetic and semisynthetic analogs of epothilones: chemistry and biological activity, in Anticancer Agents: Frontiers in Cancer Chemotherapy, ACS Symposium Series 796 (eds I. Ojima, G.D. Vite, and K.-H. Altmann), American Chemical Society, Washington, DC, pp. 112-130.
90. Altmann, K-.H., Bold, G., Caravatti, G., Denni, D., Flörsheimer, A., Schmidt, A., Rihs, G., and Wartmann, M. (2002) The total synthesis and biological assessment of trans-epothilone A. Helvetica Chimica Acta, 85, 4086-4110.
91. Nicolaou, K.C., Ninkovic, S., Finlay, M.R.V., Sarabia, F., and Li, T.H. (2004) Total synthesis of 26-hydroxyepothilone B and related analogs. Chemical Communications, 2343-2344.
92. Nicolaou, K.C., Sarabia, F., Ninkovic, S., Finlay, M.R.V., and Boddy, C.N.C. (1998) Probing the ring size of epothilones: total synthesis of [14]-, [15]-, [17]-, and [18] epothilones A. Angewandte Chemie -International Edition, 37, 81-84.
93. Altmann, K.-H., Bold, G., Caravatti, G., End, N., Flörsheimer, A., Guagnano, V., O'Reilly, T., and Wartmann, M. (2000) Epothilones and their analogs: potential new weapons in the fight against cancer. Chimia, 54, 612-621.
94. Klar, U., Skuballa, W., Buchmann, B., Schwede, W., Bunte, T., Hoffman, J., and Richtner, R. (2001) Synthesis and biological activity of epothilones, in Anticancer Agents: Frontiers in Cancer Chemotherapy, ACS Symposium Series 796 (eds I. Ojima, G.D. Vite, and K.-H. Altmann), American Chemical Society, Washington, DC, pp. 131-147.
95. End, N., Furet, P., vanCampenhout, N., Wartmann, M., and Altmann, K.-H. (2004) Total synthesis and biological evaluation of a C(10)/C(12)-phenylene-bridged analog of epothilone D. Chemistry & Biodiversity, 1, 1771-1784.
96. Arslanian, R.L., Tang, T., Blough, S., Ma, W., Qiu, R.Q., Katz, L., and Carney, J.R. (2002) A new cytotoxic epothilone from modified polyketide synthases heterologously expressed in Myxococcus xanthus. Journal of Natural Products, 65, 1061-1064.
97. Starks, C.M., Zhou, Y.Q., Liu, F.H., and Licari, P.J. (2003) Isolation and characterization of new epothilone analogues from recombinant Myxococcus xanthus fermentations. Journal of Natural Products, 66, 1313-1317.
98. Biswas, K., Lin, H., Njardarson, J.T., Chappell, M.D., Chou, T.C., Guan, Y.B., Tong, W.P., He, L.F., Horwitz, S.B., and Danishefsky, S.J. (2002) Highly concise routes to epothilones: the total synthesis and evaluation of epothilone 490. Journal of the American Chemical Society, 124, 9825-9832.
99. Rivkin, A., Yoshimura, F., Gabarda, A.E., Cho, Y.S., Chou, T.C., Dong, H.J., and Danishefsky, S.J. (2004) Discovery of (E)-910-dehydroepothilones through chemical synthesis: on the emergence of 26-trifluoro-(E)-910-dehydro-12,13-desoxyepothilone B as a promising anticancer drug candidate. Journal of the American Chemical Society, 126, 10913-10922.
100. Rivkin, A., Cho, Y.S., Gabarda, A.E., Yoshimura, F., and Danishefsky, S.J. (2004) Application of ring-closing metathesis reactions in the synthesis of epothilones. Journal of Natural Products, 67, 139-143.
101. Rivkin, A., Biswas, K., Chou, T.C., and Danishefsky, S.J. (2002) On the introduction of a trifluoromethyl substituent in the epothilone setting: chemical issues related to ring forming olefin metathesis and earliest biological findings. Organic Letters, 4, 4081-4084.
102. Rivkin, A., Njardarson, J.T., Biswas, K., Chou, T.C., and Danishefsky, S.J. (2000) 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. The Journal of Organic Chemistry, 67, 7737-7740.
103. Rivkin, A., Yoshimura, F., Gabarda, A.E., Chou, T.C., Dong, H.J., Tong, W.P., and Danishefsky, S.J. (2003) Complex target-oriented total synthesis in the drug discovery process: the discovery of a highly promising family of second generation epothilones. Journal of the American Chemical Society, 125, 2899-2901.
104. Yoshimura, F., Rivkin, A., Gabarda, A.E., Chou, H.J., Dong, H.J., Sukenick, G., Morel, F.F., Taylor, R.E., and Danishefsky, S. J. (2003) Synthesis and conformational analysis of (E)-910-dehydroepothilone B: a suggestive link between the chemistry and biology of epothilones. Angewandte Chemie -International Edition, 42, 2518-2521.
105. Chou, T.C., Dong, H.J., Rivkin, A., Yoshimura, F., Gabarda, A.E., Cho, Y.S., Tong, W.P., and Danishefsky, S.J. (2003) Design and total synthesis of a superior family of epothilone analogues which eliminate xenograft tumors to a nonrelapsable state. Angewandte Chemie -International Edition, 42, 4762-4767.
106. Rivkin, A., Chou, T.C., and Danishefsky, S.J. (2005) On the remarkable antitumor properties of fludelone: how we got there. Angewandte Chemie -International Edition, 44, 2838-2850.
107. Chou, T.C., Dong, H.J., Zhang, X.G., Tong, W.P., and Danishefsky, S.J. (2005) Therapeutic cure against human tumor xenografts in nude mice by a microtubule stabilization agent fludelone via parenteral or oral route. Cancer Research, 65, 9445-9454.
108. Chou, T.-C., Zhang, X., Zhong, Z.-Y., Li, Y., Feng, L., Eng, S., Myles, D.M., Johnson, R., Jr., Wu, N., Yin, Y.I., Wilson, R.M., and Danishefsky, S.J. (2005) Therapeutic effect against human xenograft tumors in nude mice by the third generation microtubule stabilizing epothilones. Proceedings of the National Academy of Sciences of the United States of America, 105, 13157-13162.
109. Schinzer, D., Böhm, O., Altmann, K.-H., and Wartmann, M. (2004) Synthesis and biological evaluation of furano-epothilone C. Synlett, 1375-1378.
110. Nicolaou, K.C., Scarpelli, R., Bollbuck, B., Werschkun, B., Pereira, M.M.A., Wartmann, M., Altmann, K.-H., Zaharevitz, D., Gussio, R., and Giannakakou, P. (2000) Chemical synthesis and biological properties of pyridine epothilones. Chemistry & Biology, 7, 593-599.
111. Nicolaou, K.C., Pratt, B.A., Arseniyadis, S., Wartmann, M., and O'Brate, A. (2006) Molecular design and chemical synthesis of a highly potent epothilone. ChemMedChem, 1, 41-44.
112. Nicolaou, K.C., Hepworth, D., King, N.P., Finlay, M.R.V., Scarpelli, R., Pereira, M.M. A., Bollbuck, B., Bigot, A., Werschkun, B., and Winssinger, N. (2000) Total synthesis of 16-desmethylepothilone B, epothilone B10, epothilone F, and related side chain modified epothilone B analogues. Chemistry -A European Journal, 6, 2783-2800.
113. Sefkow, M. and Höfle, G. (1998) Substitutions at the thiazole moiety of epothilone. Heterocycles, 48, 2485-2488.
114. Nicolaou, K.C., Finlay, M.R.V., Ninkovic, S., King, N.P., He, Y., Li, T.H., Sarabia, F., and Vourloumis, D. (1998) Synthesis and biological properties of C12,13-cyclopropyl-epothilone A and related epothilones. Chemistry & Biology, 5, 365-367.
115. Höfle, G., Glaser, N., Kiffe, M., Hecht, H.J., Sasse, F., and Reichenbach, H. (1999) N-Oxidation of epothilone A-C and O-acyl rearrangement to C-19- and C-21-substituted epothilones. Angewandte Chemie -International Edition, 38, 1971-1974.
116. Nicolaou, K.C., King, N.P., Finlay, M.R.V., He, Y., Roschangar, F., Vourloumis, D., Vallberg, H., Sarabia, F., Ninkovic, S., and Hepworth, D. (1999) Total synthesis of epothilone E and related side-chain modified analogues via a Stille coupling based strategy. Bioorganic & Medicinal Chemistry, 7, 665-697.
117. Erdélyi, M., Pfeiffer, B., Hauenstein, K., Fohrer, J., Gertsch, J., Altmann, K.-H., and Carlomagno, T. (2008) The conformational preferences of natural and C3-modified epothilones in aqueous solution. Journal of Medicinal Chemistry, 51, 1469-1473.
118. Kolman, A. (2004) BMS-310705 Bristol-Myers Squibb/GBF. Current Opinion in Investigational Drugs, 5, 1292-1297.
119. Kamath, A.V., Chang, M., Lee, F.Y., Zhang, Y.P., and Marathe, P.H. (2005) Preclinical pharmacokinetics and oral bioavailability of BMS-310705, a novel epothilone B analog. Cancer Chemotherapy and Pharmacology, 56, 145-153.
120. Altmann, K.-H., Bold, G., Caravatti, G., Florsheimer, A., Guagnano, V., and Wartmann, M. (2000) Synthesis and biological evaluation of highly potent analogues of epothilones B and D. Bioorganic & Medicinal Chemistry Letters, 10, 2765-2768.
121. Bold, G., Wojeik, S., Caravatti, G., Lindauer, R., Stierlin, C., Gertsch, J., Wartmann, M., and Altmann, K.-H. (2006) Structure-activity relationships in side-chain-modified epothilone analogues: how important is the position of the nitrogen atom? ChemMedChem, 1, 37-40.
122. Dietrich, S., Lindauer, R., Stierlin, C., Gertsch, J., Matesanz, R., Notararigo, S., Díaz, J.F., and Altmann, K.-H. (2009) Epothilone analogs with benzimidazole and quinoline side chains: chemical synthesis, antiproliferative activity, and interactions with tubulin. Chemistry -A European Journal, 15, 10144-10157.
123. Carlomagno, T., Blommers, M.J.J., Meiler, J., Jahnke, W., Schupp, T., Petersen, F., Schinzer, D., Altmann, K.-H., and Griesinger, C. (2003) 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. Angewandte Chemie -International Edition, 42, 2511-2515.
124. Dong, S.D., Sundermann, K., Smith, K.M.J., Petryka, J., Liu, F.H., and Myles, D. C. (2004) Rapid access to epothilone analogs via semisynthetic degradation and reconstruction of epothilone D. Tetrahedron Letters, 45, 1945-1947.
125. Hoffmann, J., Vitale, I., Buchmann, B., Galluzzi, L., Schwede, W., Senovilla, L., Skuballa, W., Vivet, S., Lichtner, R.B., Vicencio, J.M., Panaretakis, T., Siemeister, G., Lage, H., Nanty, L., Hammer, S., Mittelstaedt, K., Winsel, S., Eschenbrenner, J., Castedo, M., Demarche, C., Klar, U., and Kroemer, G. (2008) Improved cellular pharmacokinetics and pharmacodynamics underlie the wide anticancer activity of sagopilone. Cancer Research, 68, 5301-5308.
126. Klar, U., Hoffmann, J., and Giurescu, M. (2008) Sagopilone (ZK-EPO): from a natural product to a fully synthetic clinical development candidate. Expert Opinion on Investigational Drugs, 11, 1735-1748.
127. Hammer, S., Sommer, A., Fichtner, I., Becker, M., Rolff, J., Merk, J., Klar, U., and Hoffmann, J. (2010) Comparative profiling of the novel epothilone sagopilone in xenografts derived from primary non-small cell lung cancer. Clinical Cancer Research, 16, 1452-1465.
128. Hoffmann, J., Fichtner, I., Lemm, M., Lienau, Ph., Hess, H., Rotgeri, A., Hofmann, B., and Klar, U. (2009) Sagopilone crosses the blood-brain barrier in vivo to inhibit brain tumor growth and metastases. Neuro-Oncology, 11, 158-166.
129. Klar, U., Röhr, B., Kuczynski, F., Schwede, W., Berger, M., Skuballa, W., and Buchmann, B. (2005) Efficient chiral pool synthesis of the C1-C6 fragment of epothilones. Synthesis, 2, 301-305.
130. Klar, U. and Platzek, J. (2012) Asymmetric total synthesis of the epothilone sagopilone: from research to development. Synlett, 1291-1299.
131. Edelman, M. and Shvartsbeyn, M. (2012) Epothilones in development for non-small-cell lung cancer: novel anti-tubulin agents with the potential to overcome taxane resistance. Clinical Lung Cancer, 13, 171-180.
132. DeConti, R.C., Algazi, A.P., Andrews, S., Urbas, P., Born, O., Stoeckigt, D., Floren, L., Hwang, J., Weber, J., Sondak, V.K., and Daud, A.I. (2010) Phase II trial of sagopilone, a novel epothilone analog in metastatic melanoma. British Journal of Cancer, 103, 1548-1553.
133. Cachoux, F., Isarno, T., Wartmann, M., and Altmann, K.-H. (2005) Scaffolds for microtubule inhibition through extensive modification of the epothilone template. Angewandte Chemie -International Edition, 44, 7469-7473.
134. Feyen, F., Cachoux, F., Gertsch, J., Wartmann, M., and Altmann, K.-H. (2008) Epothilones as lead structures for the synthesis-based discovery of new chemotypes for microtubule stabilization. Accounts of Chemical Research, 41, 21-31.
135. Cachoux, F., Isarno, T., Wartmann, M., and Altmann, K.-H. (2006) Total synthesis and biological assessment of benzimidazole-based analogues of epothilone A: ambivalent effects on cancer cell growth inhibition. ChemBioChem, 7, 54-57.
136. Cachoux, F., Isarno, T., Wartmann, M., and Altmann, K.-H. (2006) Total synthesis and biological assessment of cyclopropane-based epothilone analogues: modulation of drug efflux through polarity adjustments. Synlett, 1384-1388.
137. Kuzniewski, C.N., Gertsch, J., Wartmann, M., and Altmann, K.-H. (2008) Total synthesis of hypermodified epothilone analogs with potent in vitro antitumor activity. Organic Letters, 10, 1183-1186.
138. Taylor, R.E., Chen, Y. and Beatty, A. (2003) Conformation-activity relationships in polyketide natural products: a new perspective on the rational design of epothilone analogues. Journal of the American Chemical Society, 125, 26-27.
139. Taylor, R.E., Chen, Y., Galvin, G.M., and Pabba, P.K. (2004) Conformation-activity relationships in polyketide natural products: towards the biologically active conformation of epothilone. Organic & Biomolecular Chemistry, 2, 127-132.
140. Zhang, W., Jiang, Y., Brodie, P.J., Kingston, D.G.I., Liotta, D.C., and Snyder, J.P. (2008) Design and synthesis of C6-C8 bridged epothilone A. Organic Letters, 10, 1565-1568.
141. Zhan, W., Jiang, Y., Sharma, S., Brodie, P.J., Bane, S., Kingston, D.G.I., Liotta, D.C., and Snyder, J.P. (2011) C6-C8 bridged epothilones: consequences of installing a conformational lock at the edge of the macrocycle. Chemistry -A European Journal, 17, 14792-14804.
142. Chen, Q.-H., Ganesh, T., Brodie, P., Slebodnick, C., Jiang, Y., Banerjee, A., Bane, S., Snyder, J.P., and Kingston, D.G.I. (2008) Design synthesis and biological evaluation of bridged epothilone D analogues. Organic & Biomolecular Chemistry, 6, 4542-4552.
143. Cachoux, F., Schaal, F., Teichert, A., Wagner, T., and Altmann, K.-H. (2004) Synthesis of 4-aza epothilone D analogs. Synlett, 2709-2712.
144. Feyen, F., Gertsch, J., Wartmann, M., and Altmann, K.-H. (2006) Design and synthesis of 12-aza-epothilones (azathilones): non-natural natural products with potent anticancer activity. Angewandte Chemie -International Edition, 45, 5880-5885.
145. Vite, G.D., Borzilleri, R.M., Kim, S.H., Regueiro-Ren, A., Humphreys, W.G., and Lee, D.Y.F. (2001) Epothilones A and B: springboards for semisynthesis of promising antimitotic agents, in Anticancer Agents: Frontiers in Cancer Chemotherapy, ACS Symposium Series 796 (eds I. Ojima, G.D. Vite, and K.-H. Altmann), American Chemical Society, Washington, DC, pp. 148-170.
146. Altmann, K-.H., Flörsheimer, A., Bold, G., Caravatti, G., and Wartmann, M. (2004) Natural product-based drug discovery: epothilones as lead structures for the development of new anticancer agents. Chimia, 58, 686-690.
147. Altmann, K.-H., Cachoux, F., Feyen, F., Gertsch, J., Kuzniewski, C.N., and Wartmann, M. (2010) Natural products as leads for anticancer drug discovery: discovery of new chemotypes of microtubule stabilizers through reengineering of the epothilone scaffold. Chimia, 64, 8-13.
148. Winkler, J.D., Holland, J.M., Kasparec, J., and Axelsen, P.H. (1999) Design and synthesis of constrained epothilone analogs: the efficient synthesis of eleven-membered rings by olefin metathesis. Tetrahedron, 55, 8199-8124.
149. Alhamadsheh, M.M., Hudson, R.A., and Tillekeratne, L.M.V. (2008) Design total synthesis and evaluation of novel open-chain epothilone analogues. Organic Letters, 8, 685-688.
150. Ojima, I., Chakravarty, S., Inoue, T., Lin, S., He, L., Horwitz, S.B., Kuduk, S.D., and Danishefsky, S.J. (1999) A common pharmacophore for cytotoxic natural products that stabilize microtubules. Proceedings of the National Academy of Sciences of the United States of America, 96, 4256-4261.
151. Ojima, I., Kuduk, S.D., Chakravarty, S., Lin, S., Wang, T., Geng, X., Miller, M.L., Bounaud, P.-Y., Michaud, E., Park, Y.H., Sun, C.-M., Slater, J.C., Inoue, T., Borella, C.P., Walsh, J.J., Bernacki, R.J., Pera, P., Veith, J.M., Bombardelli, E., Riva, A., Rao, S., He, L., Orr, G.A., Horwitz, S.B., Danishefsky, S.J., Scambia, G., and Ferlini, C. (2001) New generation taxoids and hybrids of microtubule-stabilizing anticancer agents, in Anticancer Agents: Frontiers in Cancer Chemotherapy, ACS Symposium Series 796 (eds I. Ojima, G.D. Vite, and K.-H. Altmann), American Chemical Society, Washington, DC, pp. 59-80.
152. Ojima, I., Lin, S., Inoue, T., Miller, M.L., Borella, C.P., Geng, X., and Walsh, J.J. (2000) Macrocycle formation by ring-closing metathesis. Application to the syntheses of novel macrocyclic taxoids. Journal of the American Chemical Society, 122, 5343-5353.
153. White, J.D., Smits, H., and Hamel, E. (2006) Synthesis of cryptothilone 1, the first cryptophycin-epothilone hybrid. Organic Letters, 8, 3947-3950.
154. Matsuya, Y., Kobayashi, Y., Kawaguchi, T., Hori, A., Watanabe, Y., Ishihara, K., Ahmed, K., Wei, A.-L., Yu, D.-Y., Zhao, Q.-L., Kondo, T., and Nemoto, H. (2009) Design synthesis and biological evaluation of artificial macrosphelides in the search for new apoptosis-inducing agents. Chemistry: A European Journal, 15, 5799-5813.
155. Matsuya, Y., Kawaguchi, T., Ishihara, K., Ahmed, K., Zhao, Q.-L., Kondo, T., and Nemoto, H. (2006) Synthesis of macrosphelides with a thiazole side chain: new antitumor candidates having apoptosis-inducing property. Organic Letters, 8, 4609-4612.
156. Wang, M.M., Xia, X.Y., Kim, Y., Hwang, D., Jansen, J.M., Botta, M., Liotta, D.C., and Snyder, J.P. (1999) A unified and quantitative receptor model for the microtubule binding of paclitaxel and epothilone. Organic Letters, 1, 43-46.
157. Manetti, F., Forli, S., Maccari, L., Corelli, F., and Botta, M. (2003) 3D QSAR studies of the interaction between beta-tubulin and microtubule stabilizing antimitotic agents (MSAA). A combined pharmacophore generation and pseudoreceptor modeling approach applied to taxanes and epothilones. Il Farmaco, 58, 357-361.
158. Reese, M., Sanchez-Pedregal, V.M., Kubicek, K., Meiler, J., Blommers, M.J.J., Griesinger, C., and Carlomagno, T. (2007) Structural basis of the activity of the microtubule-stabilizing agent epothilone A studied by NMR spectroscopy in solution. Angewandte Chemie -International Edition, 46, 1864-1868.
159. Erdélyi, M., Navarro-Vázquez, A., Pfeiffer, B., Kuzniewski, C.N., Felser, A., Widmer, T., Gertsch, J., Pera, B., Díaz, J.F., Altmann, K.-H., and Carlomagno, T. (2010) The binding mode of side chain- and C3-modified epothilones to tubulin. ChemMedChem, 5, 911-920.
160. Rusinska-Roszak, D. and Lozynski, M. (2009) De(side chain) model of epothilone: bioconformer interconversions DFT study. Journal of Molecular Modeling, 15, 859-869.
161. Rusinska-Roszak, D., Tatka, H., Pawlak, R., and Lozynski, M. (2011) Extended and clustered conformers of epothilone A. The Journal of Physical Chemistry. B, 115, 3698-3707.
162. Forli, S., Manetti, F., Altmann, K.-H., and Botta, M. (2010) Evaluation of novel epothilone analogues by means of a common pharmacophore and a QSAR pseudoreceptor model for taxanes and epothilones. ChemMedChem, 5, 35-40.