THE CHEMISTRY AND BIOLOGY OFEPOTHILONES—LEADSTRUCTURES FOR THE DISCOVERY OF IMPROVED MICROTUBULE INHIBITORS - Medicinal Chemistry of Bioactive Natural Products - page 13

between C11 and C12 (thus creating a 17-membered ring) without substantial loss
in antiproliferative activity. Thus, in contrast to previously studied ring-expanded
analogs (vide supra; Ref. 76), compound 9 is only four-fold less active against
the human leukemia cell line CCRF-CEM than the parent compound Epo D. 84

S

OH

N

O

O HO

9

As for other modifications in the Northern part of the epothilone macrocycle, the
replacement of C10 by oxygen has recently been shown to be detrimental for bio-
logical activity, 94 whereas the incorporation of a furan moiety incorporating C8,
C9, and C10 seems to be better tolerated. 95

1.3.3 Modifications of the Epoxide Moiety

A large part of the early SAR work on epothilones has focused on modifications
of the epoxide moiety at positions 12/13 of the macrolactone ring. These studies
have demonstrateded that the presence of the epoxide ring is not an indispensible
prerequisite for efficient microtubule stabilization and potent antiproliferative acti-
vity. Thus, Epo C (10) and D (11) (Figure 1-1) are virtually equipotent inducers of
tubulin polymerization as Epo A and B, respectively. They are also potent inhibitors
of human cancer cell growth in vitro, 20,45,62,96-99 although antiproliferative activity
is somewhat reduced in comparison with the corresponding parent epoxides. For

R

S

HO

N

O

O OH O

R = H: Epothilone C (Deoxyepothilone A) 10
(IC 50 KB-31: 25.9 nM )

R = CH 3 : Epothilone D (Deoxyepothilone B) 11
(IC 50 KB-31: 2.70 nM)

Figure 1-1. Molecular structures of deoxyepothilones. Numbers in parentheses are
IC 50 -value for growth inhibition of the human epidermoid carcinoma cell line KB-31.
Data are from Altmann et al. 45