Chemistry Reference
In-Depth Information
O
O
AcO
OH
HO
OH
Bu
t
OCON
PhCON
H
O
O
H
H
O
H
O
Ph
O
Ph
O
AcO
AcO
OH
OH
OH
OH
OCOPh
OCOPh
15
14
O
HO
OH
O
HO
H
O
O
OH
O
PhCOO
PhCON
H
O
16
Figure 13.5
Structures of paclitaxel (Taxol), docetaxel, and britaxel-5.
Numerous analogs and prodrugs of paclitaxel have been developed, and several
of these are in clinical trials. Full coverage of these compounds is beyond the
scope of this chapter, but additional details are provided in a recent review (33).
As of early 2007, the only new form of paclitaxel in clinical use is the albumin-
bound paclitaxel known as Abraxane (Abraxis BioScience, Schaumberg, IL) (34).
The binding of paclitaxel to microtubules has been studied extensively. The
polymeric and noncrystalline nature of the tubulin - taxol complex prevents a
direct approach by X-ray crystallography, but Lowe et al. (35) could determine
the structure of tubulin at 3.5 A resolution by electron diffraction. Using this
structure, various possible binding orientations of paclitaxel on tubulin have been
proposed, but recent REDOR NMR studies have established T-Taxol as the most
probable conformation (36). The synthesis of the highly active bridged analog
britaxel-5 (
16
), which is constrained to a T-Taxol conformation, confirmed this
hypothesis (37).
13.2.2.2 Epothilones
The epothilones A-D (
17
-
20
) were isolated from the
myxobacterium
Sorangium cellulosum
as antifungal agents (38), but they were
found subsequently to have the same mechanism of action as paclitaxel, which
promotes the assembly of tubulin into microtubules (39). The epothilones are
thus of great interest as potential antitumor agents because of their mecha-
nism of action and because they are also active against some paclitaxel-resistant
cell lines. At first glance, they would seem to have a very different shape
