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in long-lasting regressions and cures in a Taxol-resistant KB-8511 epidermoid car-
cinoma model.
1.3.6
Aza-Epothilones
Of the numerous epothilone analogs recently reported in the literature, only a few
are characterized by the replacement of carbon atoms in the macrocyclic skeleton
by heteroatoms, and those investigated to date were found to be poorly active
(for examples, see Refs. 69, 94, and 120). Overall, however, the potential of such
modifications remains largely unexplored, which is despite the fact that the replace-
ment of carbon by heteroatoms in complex structures could lead to improved syn-
thetic accessibility and offer the potential to generate large sets of diverse analogs
in a straightforward manner (e.g., through amide bond formation or reductive ami-
nation in the case of nitrogen). In light of this fact and guided by the potent bio-
logical activity associated with the deoxyepothilone structural framework
(vide supra), some of our initial work in the area of epothilone modifications
was directed at the replacement of the C12/C13 olefinic double bond in Epo D
by N-alkyl amides and 1,2-disubstituted heterocycles, such as imidazole. Structural
units of this type were hypothesized to act as cis C
C double bond mimetics and
thus to result in a similar conformation of the macrocycle as for Epo D (assuming a
preference of the C-N partial double bond for a cis conformation). As a conse-
quence, such analogs were expected to exhibit similar antiproliferative activities
as the parent deoxyepothilones. At the same time, these polar double bond substi-
tutes were assumed to lead to improved aqueous solubility of the corresponding
analogs over the very lipophilic Epo D.
R
N
N
O
N
S
S
HO
HO
N
N
O
O
OH
O
O
O
OH
O
(37)
R = CH
3
:
(34)
R = C
2
H
5
:
(35)
R = H:
(36)
Unfortunately, none of the analogs 34, 35, 37,or(N-unsubstituted secondary
amide) 36, which would mimic a trans-olefin geometry) showed any appreciable
tubulin-polymerizing or antiproliferative activity, despite the fact that preliminary
NMR studies with compound (34) in DMSO/water indicate that the preferred con-
formation about the 12/13 N-methyl amide bond is indeed cis, that is, the methyl
group and the carbonyl oxygen are located on the same side of the partial C-N
double bond (cis/trans-ratio
4/1; 34 may thus be considered a direct structural
mimetic of Epo D). The underlying reasons for the lack of biological activity of
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