Chemistry Reference
In-Depth Information
(12S,13S) trans-epothilone A (19) in fact shows slightly higher growth inhibitory
activity than Epo A, and we have observed this rank order of activity across a wide
range of human cancer cell lines, which makes this compound an interesting can-
didate for in vivo profiling (e.g., average IC
50
values across a panel of seven human
cancer cell lines of 2.72, 0.30, and 1.32 nM have been reported for Epo A, Epo B,
and 19, respectively
105
). Whether the cis/trans equivalence observed for Epo A and
trans-epothilone A (19) also occurs in the Epo B series is unclear at this point, as
the literature data on this question are somewhat contradictory (an 88-fold activity
difference between Epo B and trans-Epo B against the human ovarian cancer cell
line 1A9 is reported in,
98
whereas a difference of only 8-fold is reported in Ref. 99
for the same cell line; cf. also Ref. 106). On the other hand, our finding that the
trans-Epo A scaffold of 19 is associated with potent biological activity has recently
been confirmed and expanded by Nicolaou et al. for a series of highly potent
C12/C13 cyclopropane-based analogs of 19.
103,106
1.3.4
C-26-Modified Analogs
In addition to the changes in the epoxide structure, a variety of modifications of the
26-methyl group in Epo B or D have been reported. These studies have shown that
the replacement of one hydrogen atom of this methyl group by relatively small and
apolar substituents such as F, Cl, CH
3
,orC
2
H
5
(Figure 1-3, X
¼
CH
2
F, CH
2
Cl,
C
2
H
5
, n-C
3
H
7
), is well tolerated, thus producing analogs that are only slightly
less potent in vitro than Epo B or Epo D.
62,99,107
In general, activity decreases with increasing size of the C26-substituents,
62,99
but
exceptions
from
this
general
theme
have
been
reported
recently.
Thus,
X
X
O
S
S
HO
N
HO
N
O
O
O
OH
O
O
OH
O
O
F
O
O
S
S
HO
HO
N
N
O
O
O HO
O
HO
20
21
Figure 1-3. Molecular structures of C-26-modified analogs of Epo B and D. For meaning of
X, see the text.
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