THE CHEMISTRY AND BIOLOGY OFEPOTHILONES—LEADSTRUCTURES FOR THE DISCOVERY OF IMPROVED MICROTUBULE INHIBITORS - Medicinal Chemistry of Bioactive Natural Products - page 10

be significantly more stable in human than in rodent plasma, 72 which is in line with
our studies on Epo B and clearly is a result of the well-known difference in plasma
esterase activity between humans and rats or mice. BMS-247550 (1) is a potent
inducer of tubulin polymerization, but its antiproliferative activity is circa one order
of magnitude lower than that of Epo B 37,70 (e.g., IC 50 values against the human
colon carcinoma cell line HCT-116 are 3.6 nM and 0.42 nM, respectively, for
1 and Epo B 70 ). Methylation of the lactam nitrogen has been shown to result in
a substantial loss in potency. 73
In contrast to Epo B, 1 exhibits a significant activity differential between the
drug-sensitive KB-31 cell line and its P-gp overexpressing multidrug-resistant
KB-8511 variant (IC 50 's of 2.85 nM and 128 nM against KB-31 and KB-8511 cells,
respectively 37 ), thus indicating that the compound is a substrate for the P-gp efflux
pump. Similar differences between P-gp-overexpressing and drug-sensitive human
cancer cell lines have been observed for lactam-based analogs of Epo C and D. 73,74
Like other types of microtubule inhibitors, BMS-247550 (1) was found by Yama-
guchi et al. to induce G2/M arrest and apoptosis in human cancer cell lines. 75 Inter-
estingly, BMS-247550-induced cell death, at least in MDA-MB 468 breast
carcinoma cells, seems to be caspase-dependent, 75 contrary to what has been
reported for Epo B in other cell lines. 53-55 It is also worth noting that Yamaguchi
et al. strongly emphasize that [BMS-247550 (1)-induced] ''apoptosis of A2780-1A9
cells follows mitotic arrest, which is not associated with a marked increase in the
levels of survivin'' (cf., however, recent work by Chen et al. 51,52 ).
BMS247550 (1) exhibits antitumor activity similar to that of Taxol in Taxol-
sensitive tumor models (i.e., A2780 human ovarian carcinoma, HCT116 and
LS174T human colon carcinomas) when each drug is given at its optimal dose. 71
Despite its limited effects against highly multidrug-resistant cell lines in vitro, 1 was
also shown to be superior to Taxol in Taxol-resistant tumor models (i.e., Pat-7 and
A2780Tax human ovarian carcinomas, Pat-21 human breast carcinoma, and Pat-
26 human pancreatic carcinoma, and M5076 murine sarcoma). Furthermore, the
compound showed remarkable antitumor activity against Pat-7 ovarian and HCT-
116 colon carcinoma xenografts after oral administration. 71

1.3.2 Modifications in the C9-C12 Region

Initial reports on structural modifications in the C9-C11 trimethylene fragment
adjacent to the epoxide moiety were rare, and the corresponding analogs were
generally found to exhibit diminished biological activity. Early work by the Nicolaou
and Danishefsky groups had shown that ring contraction or expansion via the removal
of existing or the incorporation of additional CH 2 -groups in the C9-C11 region
causes a substantial loss in biological potency. 62,76 An alternative approach pursued
in our laboratory for modifications situated in the Northern hemisphere of epothilones
was based on an epothilone pharmacophore model, which was derived from
a comparative analysis of the x-ray crystal structure of Epo B 13 with those of
paclitaxel and discodermolide (P. Furet and N. Van Campenhout, unpublished results)
(see Refs. 57 and 77-80). According to this model, the bioactive conformation of