STRUCTURE MODIFICATIONS AND THEIR INFLUENCES ON ANTITUMOR AND OTHER RELATED ACTIVITIES OF TAXOL AND ITS ANALOGS - Medicinal Chemistry of Bioactive Natural Products - page 87

3.2.3 B Ring and Its Substitutions

3.2.3.1 C-10 Substitutions
Generally, C-10 deacetylation or deoxygenation made an insignificantly negative
and positive contribution to the cytotoxicity against sensitive tumor cells, respec-
tively, by comparison with paclitaxel.
For different acyl groups at the C-10 position, it was thought previously that
change from acetyl in paclitaxel to other acyl groups usually did not affect the
activity significantly and even improve the activity sometimes. Recently, Liu et al.
constructed a library with C-10-modified paclitaxel analogs, in which aliphatic, het-
eroatom-containing aliphatic, alicyclic, aromatic, heteroaromatic acyl groups were
introduced. 40 These taxoids were less active in both tubulin assembly and B16 mel-
anoma cytotoxicity assays. Quite different from Liu et al. results, Kingston et al.
found C-10 propionate, isobutyrate, and butyrate of paclitaxel were more active
against A2780 human ovarian cancer. 64 They investigated the effects of simulta-
neous modification of analogs at C3 0 -N/C-2 and C-10/C-2 positions. 65
Interestingly, either reduction or the synergistic effect was observed in this study.
For example, simultaneous introduction of C-10 substitutions with positive
effects, that is, propionate or cortonate, to the C-2 m-substituted benzoyl taxoids
did not improve or even reduce activity in comparison with C-2 m-substituted
benzoyl taxoids (37b-c vs. 37a). In addition, taxoid 38 with the C-10 propanoyl
and C-3 0 -N furoyl group increased activity unexpectedly, which infers a synergistic
effect.

RO

Bz

O

O

NH O

OH

O

Ph O

O

O

OH

NH O

OH

O

HO

H

O

O

Ph O

OAc

O

OH

HO

H

O

BzO

R'

OAc

37a R=Ac
37b R= i -PrCO
37c R=Crotonyl

38

Datta et al. synthesized 10-epi and 9a-OH paclitaxel analogs by iterative
oxidation-reduction transformations, furnishing 39-41. 10-Epi paclitaxel 39a and
10-deacetyl paclitaxel 39b are slightly more active than paclitaxel in both cytotoxi-
city and tubulin binding assays, whereas their 9(R) counterparts 40 are comparable
or slightly less active. 10-Keto analog 41 is also comparable with paclitaxel in both
assays. 66