STRUCTURE MODIFICATIONS AND THEIR INFLUENCES ON ANTITUMOR AND OTHER RELATED ACTIVITIES OF TAXOL AND ITS ANALOGS - Medicinal Chemistry of Bioactive Natural Products - page 124

role of the C-13 side chain, but some pharmacophore studies have suggested that
the C-13 isoserine chain only contributes a small part compared with the baccatin
core structure, to binding and triggering subsequent physiological response. 160,164,165
Replacement with a much more simple C-13 side chain is expected to furnish a new
generation of antitumor taxanes. On the basis of common pharmacophore estab-
lished for paclitaxel and several other tubulin-targeting molecules, people tried to
apply SAR results of one drug, such as paclitaxel, to another molecule sharing the
same pharmacophore. But such efforts were usually unsuccessful (it has been
shown recently that these antitubulin agents may not share a common pharmaco-
phore). Instead, high throughput screening of small molecule libraries with struc-
ture diversity may be a good choice in the future discovery of antitubulin
compounds. 260 The discovery of other mechanisms of taxoids, such as apoptosis
and stimulation of the immune system, will prompt people to find new synergic
use of taxoids with other drugs.
It is expected that our SAR and mechanistic knowledge will lead to the rational
design of the next generation of taxoids with better properties in the future. New
techniques including combinatorial chemistry, genomics, and proteomics will
reshape the pharmaceutical industry in the future and accelerate the research and
development of new drugs and, undoubtedly, benefit taxoid research.
Notes
After this manuscript was prepared, an important article appeared that should be
cited here. 261
Based on analysis of electronic crystallography and NMR data for the bindings
of Taxol and epothilone A to tubulin subunits, it was proposed that they did not
share a common pharmacophore (similar binding mode and sites) as hypothesized
for a long time, because they bind to their receptors uniquely and independently.
Also, the T-shape conformation of Taxol binding to tubulin was supported from
this study.
ACKNOWLEDGMENTS
We thank Ms. Chun-yan Han and Xiao-yan Tian for their assistance in drawing
strutures. Our taxoid research project is supported by the Foundation for the Author
of National Excellent Doctoral Dissertation of P.R. China (Grant 199949).
REFERENCES
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