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be potent antiproliferative agents. Interestingly, however, some of these analogs are
significantly less active against the multidrug-resistant KB-8511 line than the drug-
sensitive KB-31 parental line, thus indicating that compounds 38 are better P-gp
substrates than natural epothilones. The structural basis for this phenomenon is
not understood at this point, but the finding is in line with a more general tendency
for polar epothilone analogs (e.g., compounds incorporating (other) amide bonds or
additional hydroxyl groups) to exhibit increased resistance factors in the KB-31/
KB-8511 cell line pair (i.e., increased ratios of IC
50
(KB-8511)/IC
50
(KB-31); M.
Wartmann and K.-H. Altmann, unpublished observations). The most interesting of
the compounds included in Table 1-2 is analog 38a, which is only circa 15-fold less
active against the drug-sensitive KB-31 line than Epo A (and thus roughly equipo-
tent with Epo C) and is characterized by an only modest resistance factor of
3.
This analog also shows measurable induction of tubulin polymerization in vitro, but
it remains to be determined whether the antiproliferative activity of 38a is mainly
related to interference with microtubule functionality or whether other/additional
mechanisms may also be operative.
A third type of aza-epothilones, which we have investigated as part of our pro-
gram on backbone-modified hetero-analogs of epothilones, is characterized by the
replacement of C4 by nitrogen and the presence of a C5/N4 amide group rather than
a C5-ketone (39; Ref. 126). These analogs were inspired by the fact that one of the
characteristic features of the tubulin-bound structure of Epo A
93
is the presence of a
syn-periplanar conformation about the C4-C5 bond. The same geometry would be
enforced in analogs of type 39, provided that the amide bond between N4 and C5
would be present in a cis conformation. At the same time, preliminary modeling
studies indicated that the presence of a cis amide bond in this position should allow
replacement of the C1-C4 segment by various types of b-amino acids without caus-
ing significant distortions in the bioactive conformation of the C5-O16 segment.
Apart from these structural considerations, structures of type 39 also appeared
attractive for chemical reasons, as they would lend themselves to an efficient com-
binatorial chemistry approach employing a single advanced intermediate (i.e., a
C5-carboxylic acid encompassing the C21-C5 fragment 40; epothilone numbering).
S
S
HO
TBSO
N
N
R
N
O
OH
OTES
O
O
O
39
40
So far, only a few examples of analogs of type 39 have been investigated, all of
which were found to lack any meaningful tubulin polymerizing or antiproliferative
activity.
126
However, many of these structures (incorporating different types of
a-, b-, and g-amino acids) will need to be investigated before allowing a final
conclusion on the (pharmaceutical) validity of this modification approach. Based
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