THE CHEMISTRY AND BIOLOGY OFEPOTHILONES—LEADSTRUCTURES FOR THE DISCOVERY OF IMPROVED MICROTUBULE INHIBITORS - Medicinal Chemistry of Bioactive Natural Products - page 19

and 22, this is not necessarily the case for BMS-247550 (1), which thus renders the
interpretation of these comparisons problematic.
C21-Amino-Epo B [BMS-310705 (23)] is undergoing clinical evaluation in
humans, but only limited biological data are currently available in the literature
for this compound. Thus, an IC 50 value of 0.8 nM for growth inhibition of the
human epidermoid cancer cell line KB.31 has been reported in a patent applica-
tion 118 (vs 1.2 nM for Epo B under comparable experimental conditions 111 ).
More recently, Uyar et al. 119 have demonstrated that 50 nM BMS-310705 induces
substantial apoptosis in early passage ovarian cancer cells (OC-2), which were
derived from a clinical tumor sample and were refractory to paclitaxel and platinum
treatment. A concentration of 50 nM of BMS-310705 (23) is clinically achievable at
a dose of 10 mg/m 2 , which is below the phase I maximum tolerated dose (MTD) for
the compound. 39,119 BMS-310705 (23) exhibits improved water-solubility over
BMS-247550 (1), which enables the use of clinical formulations not containing
Cremophor-EL. 39
Major contributions to the area of heterocycle modifications in epothilones have
come from the collaborative work of the Nicolaou group at The Scripps Research
Institute (TSRI) in La Jolla, CA, and our group at Novartis. One of the most sig-
nificant findings of this research is that pyridine-based analog 24 (Figure 1-4) and
methyl-substituted variants thereof are basically equipotent with Epo B, 114 which
clearly demonstrates that the presence of a five-membered heterocycle attached to
C17 is not a prerequisite for highly potent biological activity.

O

Z

Y

HO

X

O

O OH O

X, Y, Z = N, CH, CH: 24 (IC 50 KB-31: 0.30 nM)
X, Y, Z = CH, N, CH: 25 (IC 50 KB-31: 4.32 nM)
X, Y, Z = CH, CH, N: 26 (IC 50 KB-31: 11.8 nM)

O

Y Z

HO

X

O

O OH O

X, Y, Z = N, N, CH: 27 (IC 50 KB-31: 8.78 nM)
X, Y, Z = N, CH, N: 28 (IC 50 KB-31: 14.9 nM)
X, Y, Z = CH, CH, CH: 29 (IC 50 KB-31: 2.88 nM)
Figure 1-4. Molecular structures of pyridinyl-, pyrimidinyl-, and phenyl-based Epo B
analogs. Numbers in parentheses are IC 50 -values for growth inhibition of the human
epidermoid carcinoma cell line KB-31. Data are from Nicolaou et al. 114 and Altmann et al. 120