Epothilones and their analogs -potential new weapons in the fight against cancer

Chimia

Volumn 54, Issue 11, 2000, Pages 612-621

  Altmann, Karl Heinz ^a   Bold, Guido ^b   Caravatti, Giorgio ^b   End, Nicole ^b   Flörsheimer, Andreas ^b   Guagnano, Vito ^b   O'Reilly, Terence ^b   Wartmann, Markus ^b  

^a NOVARTIS PHARMA AG   (Switzerland)

^b NONE

Author keywords

Antiproliferative activity; Antitumor activity; Epothilones; Pharmaceutical chemistry; Potent analogs; Structure activity relationships

Indexed keywords

EID: 0034354340     PISSN: 00094293     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Article

References (67)

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45. The absolute stereochemistry of compounds 4a/b, 5a/b, 6a/b, and 7a/b has not been explicitly determined. The stereochemical assignments shown in Scheme 1 are simply inferred from the comparison of the biological data obtained for acetonides 7a/7b and 5a/5b with the relative activities of epothilone A/epi-epothilone A (the inactive (12S, 13R) isomer of epothilone A) and (12S, 13S)/(12R, 13R) trans-epothilones A, respectively. The stereochemistry of 7a (12S, 13S) corresponds to that of the active isomer of trans-epothilone A (cf. [35]).
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47. Like azido alcohol 8 the corresponding halohydrins 8a, 8b, and 8c inhibit the growth of KB-31 and KB-8511 cells with IC50s in the nM range. (equation presented) Activity decreases in the order 8c (IC50s of 6.5 nM and 5.4 nM on KB-31 and KB-8511, respectively) > 8b (IC50s of 11.2 nM and 5.2 nM) > 8a (IC50s of 96.7 nM and 85.5 nM). In all three cases IC50s were determined for 2:1 - 4:1 mixtures of the 12-and 13-halo isomers, respectively, as no isomer separation could be achieved for any of these regioisomeric mixtures. For 8b and 8c interpretation of the biological data may additionally be complicated by the fact that these compounds under the assay conditions could conceivably revert, at least partially, to epothilone A. In preliminary experiments in aqueous phosphate buffer, pH 7/dioxane 1/1 epothilone A was regenerated from 8c (4:1 mixture of regioisomers, vide supra) with a half-life of ca. 12 d. On the other hand, 8a has been reported to be completely resistant to epoxide formation even under strongly basic conditions [17c].
48. At first glance the lack of measurable induction of tubulin polymerization by azido alcohol 8 may be taken to indicate that the antiproliferative activity of this compound is not primarily caused by interference with microtubule functionality. However, it should be kept in mind that the cellular activity of 8 is ca. 30-fold lower than that of epothilone A. Assuming a strictly linear correlation between induction of tubulin polymerization and antiproliferative activity in vitro (which is a gross oversimplification), an EC50 for induction of tubulin polymerization of ca. 30 μM would be predicted for 8 (cf. Table 1 for EC50 of epothilone A). Based on data for other compounds (e.g. 5a) EC50s in this range do not translate into tubulin polymerization values significantly above 10% at 2 μM compound concentration (if at all). Taking into consideration that cellular activity will depend not only on target affinity in vitro, the lack of tubulin polymerization induction in vitro under our specific assay conditions thus does not imply that interaction with cellular microtubules is not at the origin of the antiproliferative activity of 8.
49. We have recently completed the total synthesis of both epoxide isomers of transepothilone A and we have established the absolute stereochemistry of the epoxide moiety by X-ray crystallography (G. Caravatti et al.). The (12S, 13S)-isomer is at least equipotent to epothilone A, whereas the (12R, 13R)-isomer is more than 500-fold less active.
50. The synthesis of these analogs will be published elsewhere (K.-H. Altmann et al.).
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56. The synthesis of 14 will be published elsewhere (N. End et al.).
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62. Details of the synthesis of 22/23, including the preparation of 24 and 30, will be published elsewhere (K.-H. Altmann et al.).
63. Alkyl iodide 25 was prepared by a modification of the route described by Schinzer et al.: D. Schinzer, A. Bauer, J. Schieber. Chem.-Eur. J. 1999, 5, 2492-2500.
64. R.W. Murray, R. Jeyaraman, J. Org. Chem. 1997, 50, 2847-2853.
65. These data will be published separately (K.-H. Altmann et al.).
66. a) T.-C. Chou, X.-G. Zhang, A. Balog, D.-S. Su, D. Meng, K. Savin, J.R. Bertino, S.J. Danishefsky, Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 9642-9647;
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