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analogs 34-37 have not been elucidated, but subsequent data obtained in various
laboratories,
124,125
including ours, for other (non-amide-based) structures suggested
that increasing the steric bulk at C13 was generally associated with reduced potency. In
light of these findings, we decided to continue exploration of the potential utility of
nitrogen incorporation at position 12 of the macrocycle, as a functional handle for addi-
tional substitution, without concomitant modification of C13. At the most straightfor-
ward level, this approach involved simple acylation of the 12-nitrogen atom, which thus
lead to amide- and carbamate-based analogs of type 38, whose carbonyl oxygen could
potentially assume the role of the epoxide oxygen in natural epothilones.
R
O
N
S
HO
N
O
O
OH
O
38
Analogs 38 were tested for their ability to promote in vitro tubulin polymeriza-
tion, and their antiproliferative activity was assessed against the human epidermoid
cancer cell lines KB-31 and KB-8511, which serve as representative examples
of drug-sensitive and P-gp-overexpressing, multidrug-resistant human cancer cell
lines, respectively (see, e.g., Refs. 20 and 37).
As illustrated by the data summarized in Table 1-2, compounds of type 38,
although less active inhibitors of cancer cell growth than Epo A or B, can indeed
TABLE 1-2. Induction of Tubulin Polymerization and Growth Inhibition of Human
Carcinoma Cell Lines by 12-Aza-Epothilones 38
% Tubulin
IC
50
KB-31
IC
50
KB-8511
Polymerization
a
[nM]
b
[nM]
b
Compound
R
38a
O-tert-C
4
H
9
27
31
105
38b
OCH
2
Ph
<
10
297
703
38c
OC
2
H
5
17
85
465
38d
O-iso-C
3
H
7
<
10
297
737
N. D.
c
38e
CH
3
<
10
116
38f
C
2
H
5
<
10
71
1352
38g
tert-C
4
H
9
<
10
206
>
1000
38h
C
6
H
5
<
10
>
1000
>
1000
a
Induction of polymerization of porcine brain microtubule protein by 5 mM of test compound relative to
the effect of 25 mM of Epo B, which gave maximal polymerization (85% of protein input).
b
IC
50
values for growth inhibition of human epidermoid carcinoma cell lines KB-31 and KB-8511.
Values generally represent the average of two independent experiments.
c
Not determined.
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