STRUCTURE MODIFICATIONS AND THEIR INFLUENCES ON ANTITUMOR AND OTHER RELATED ACTIVITIES OF TAXOL AND ITS ANALOGS - Medicinal Chemistry of Bioactive Natural Products - page 123

agents. 257 Some small synthetic molecules were designed to simplify the complex
structure of paclitaxel while retaining its activity. A series of compounds with the
C-13 isoserine side chain of paclitaxel attached to a borneol derivative, an inter-
mediate of total synthesis of paclitaxel, showed good microtubule stabilizing
effects. The compound 121 was chosen for cytotoxicity test, and it is far less cyto-
toxic than paclitaxel. 258 Another interesting example is GS-164 (122) with a simple
structure. This compound exhibits many aspects similar to those of paclitaxel in
microtubule polymerization, but with three orders of magnitude reduced activity
in cytotoxic assays. 259 Recently, Haggart et al. discovered a small molecule, namely
synstab A (123), using reversed genetics or chemical genetics methodology. 260 At
first, they used an antibody-based high-throughput screening method to fish out
those compounds, which can cause mitotic arrest from a library of 16,320 com-
pounds, and then they evaluated the tubulin assembly activity of them. Those
hits were divided into a colchicine-like group, which destabilizes microtubules,
and a paclitaxel-like group, which stabilizes them. Synstab A may bind to the
same site on a microtubule as paclitaxel or change the conformation of the
microtubule to prevent paclitaxel from binding. This approach may be useful in
the discovery of antimitotic leading compounds.

F

O

O

OH

N

N

OH

O

O

NH

MeO

O

F

O

122

121

Br

H
N

H
N

CCl 3 O

O

H 2 N S

O

123

3.8 CONCLUSION

Most research has focused on the development of paclitaxel analogs or prodrugs
with enhanced specificity; MDR reversal and orally effective taxoids have also
been developed recently. Meanwhile, scientists have gained insights into the
mechanism of action of taxoids at molecular level, that is, binding sites on tubulin
and dynamics of tubulin polymerization. It is worth pointing out that the SAR
results derived from traditional medicinal chemistry 2-4 have shown the essential