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availability of this information shortly after the discovery of their mechanism of
action has provided an important impetus for the extensive synthetic chemistry
efforts on Epo A and B and their analogs over the subsequent years. Although
they are not part of this chapter, it is worth noting that a growing number of addi-
tional natural products have been recognized over the last few years to be micro-
tubule stabilizers,
7,14-18
thus providing a whole new set of diverse lead structures
for anticancer drug discovery.
While exerting their antiproliferative activity through interference with the same
molecular target, a major distinction between paclitaxel and epothilones is the abil-
ity of the latter to inhibit the growth of multidrug-resistant cancer cell lines.
11,19-21
In addtition, epothilones have also been shown to be active in vitro against cancer
cells, whose paclitaxel resistance originates from specific tubulin mutations.
19,22
At
the same time, epothilones possess more favorable biopharmaceutical properties
than paclitaxel, such as improveded water-solubility,
13
which enables the use of
clinical formulation vehicles less problematic than Cremophor EL. (For a discus-
sion of the clinical side-effects of Taxol believed to originate in this particular for-
mulation vehicle, see Ref. 5). Epo B and several of its analogs have been
demonstrated to possess potent in vivo antitumor activity, and at least five com-
pounds based on the epothilone structural scaffold are currently undergoing clinical
evaluation in humans. These compounds include Epo B (EPO906; developed by
Novartis), Epo D (deoxyEpo B, KOS-862; Kosan/Sloan-Kettering/Roche), BMS-
247550 (the lactam analog of Epo B; BMS), BMS-310705 (C21-amino-Epo B;
BMS), and ABJ879 (C20-desmethyl-C20-methylsulfanyl-Epo B; Novartis).
The combination of an attractive biological profile and comparatively limited
structural complexity (at least for a natural product) has made epothilones attractive
targets for total chemical synthesis. Thus, numerous syntheses of Epo A and B have
been published in the literature (for reviews of work up to 2001, see Refs. 23-26;
for more recent work, see Refs. 27-36) since the first disclosure of their absolute
stereochemistry in 1996.
13
At the same time, the methodology developed in the
course of those studies has been exploited for the synthesis of a host of synthetic
analogs (reviewed in Refs. 23, 24, 37-40); although structural information on com-
plexes between epothilones and their target protein b-tubulin (or microtubules) at
atomic resolution is still lacking (vide infra), this has allowed the empirical eluci-
dation of the most important structural parameters required for biological activity.
The chemistry developed for the preparation of some of these analogs should even
allow the production of amounts of material sufficient for clinical trials,
24,41
thus
highlighting the difference in structural complexity (which is reflected in synthetic
accessibility) between epothilone-type structures and paclitaxel, for which an
industrial scale synthesis is clearly out of reach.
The chemistry, biology, and structure activity relationship (SAR) of epothilones
have been extensively discussed in recent review articles.
20,23,24,37-40
It is thus not
the intention of this chapter to provide a detailed review of these different facets of
epothilone-related research. Rather, this chapter will focus on some selected aspects
of the chemistry, biology, and clinical evaluation of natural epothilones and
their synthetic analogs, with particular emphasis on SAR work performed in our
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