STRUCTURE MODIFICATIONS AND THEIR INFLUENCES ON ANTITUMOR AND OTHER RELATED ACTIVITIES OF TAXOL AND ITS ANALOGS - Medicinal Chemistry of Bioactive Natural Products - page 80

3.2.1.3 C3 0 -N Substitutions
Although some C3 0 -N-debenzoyl N-acyl paclitaxels were evaluated, the impact of
C3 0 -N substituents on antitumor activity seems to be somewhat complicated—
neither electronic effects nor steric effects alone can be applied to explain the con-
tributions of the acyl groups.
A Korean group extensively studied such analogs with aliphatic acyl groups
and found that those with conjugated double and triple bonds displayed higher
activities against both sensitive and resistant tumor cells. When a-substitutions or
b-substitutions were attached to the double bonds, reduced or enhanced activities
were observed, respectively. More importantly, they demonstrated the essential role
of the size of the acyl group. Most analogs bearing three to six carbons displayed
high potency. 32 Comparative molecular field analysis (COMFA) was then applied to
create a rational explanation and prediction protocol of SAR of C3 0 -N-acyl analogs
by this Korean group. 33 Three-dimensional contour maps were provided to predict
the distribution of seemingly scattered antitumor activities in a precise manner, and
the steric effect is regarded as the dominating factor that made up about 80% of
contributions, whereas the electrostatic effect made up about 20% of contributions.
Alietal.reported 34 the synthesis of a series of C3 0 -t-butyl paclitaxel analogs with
C3 0 -N amides and carbamates, among which N-debenzoyl-N-(2-thienoyl) analog 12
was the most potent. Although equipotent to docetaxel, and about 25 times more water
soluble than paclitaxel, this taxane was not superior to analog 13 35 reported earlier.
A BMS research group found that 3 0 -t-butylaminocarbonyloxy paclitaxel analogs
14a and 14b (regioisomers of docetaxel and its 10-Ac derivative) were several times
less active than paclitaxel in vitro, but 14b was equipotent to paclitaxel in vivo. 36
They also prepared 3 0 -N-thiocarbamate and C3 0 -N-thiourea bearing analogs. Although
C3 0 -N-thiocarbamate was found to be more potent than paclitaxel and docetaxel in both
tubulin polymerization and cytotoxicity assays, thioureas are usually less active. 37

AcO

NHBz

O

AcO

O

OH BocHN

O

O

OH

O

O

OH

HO

H OH

O

HO H

AcO

BzO O

AcO

BzO

12

13

O

RO

N
H

O

O O

OH

Ph O

OH

HO H

O

BzO

AcO

14a R=H
14b R=Ac