STRUCTURE MODIFICATIONS AND THEIR INFLUENCES ON ANTITUMOR AND OTHER RELATED ACTIVITIES OF TAXOL AND ITS ANALOGS - Medicinal Chemistry of Bioactive Natural Products - page 77

3.2.1.1 C-2 0 Position
Numerous results have demonstrated that the free 2 0 -OH is crucial to the activity. Its
replacement with other bioisosteric atoms/groups, for example, NH 2 ,F,OCH 3 ,or
deoxygenation at this position led to complete loss of activity (two to three orders
of magnitude less cytotoxic). 13,15 It was then deduced that 2 0 -OH may get involved
in hydrogen bonding to the receptor, which was confirmed later by x-ray crystal-
lography of docetaxel and its receptor tubulin complex.
Steric hindrance, that is, the introduction of (S)-Me to C-2 0 , while 2 0 (R)-OH is
retained, makes a positive contribution to the antitumor activity as well as to the
tubulin binding ability. This result may have come from the reduced rotation of
the side chain, which thus enhances the ratios of bioactive conformers in all con-
formers. 17-19 The preparation of 2 0 -Me analog was usually undertaken by b-lactam
approach, in which 3-keto-b-lactam was attacked by a nucleophile to yield stereo-
selectively 3-methyl-3-OH (equivalent to the 2 0 position in paclitaxel) b-lactam
ready for attachment to baccatin core structures. Battaglia et al. prepared a series
of 2 0 (S)-Me of paclitaxel analogs from 10-DAB and 14b-OH-10-DAB with differ-
ent C-3 0 and 3 0 -N substitutents, and all compounds 6a-e are comparable with or
more active than paclitaxel toward A2780 human lung carcinoma in vitro. 20

O

AcO

AcO

Boc

O

O

NH O

NH O

R

OH

OH

R O

O

O

OH

OH

O

HO H

H O

O

O

AcO

AcO

BzO

BzO O

6c R=2-furyl
6d R=C 6 H 5
6e R=CF 3

6a R=C 6 H 5
6b R=Me 3 CO

G ´ nisson et al. also prepared two diastereomers of 2 0 -hydroxymethyl analogs
through an asymmetric Baylis-Hillman reaction-like sequence to prepare a 3 0 (S)-
N-substituted 2 0 -methylene C-13 side chain (Scheme 3-3). After incorporation of
the side chain to C-13 of 7,10-di-Troc-10-DAB, the product was then subjected
to osmylation to yield 2 0 (R)- and 2 0 (S)-hydroxymethyl docetaxel 7a-b analogs
stereoselectively. Both taxoids displayed less tubulin polymerization abilities than
did paclitaxel, but the major product 2 0 R-isomer 7a is more active than the minor
one 2 0 S-isomer 7b. 21

3.2.1.2 C-3 0 Position
Replacement of 3 0 -Ph with other aromatic and aliphatic groups have been investi-
gated, among which three to four carbon alkyl or alkenyl substitutions, especially
3 0 -isobutenyl and 3 0 -isobutyl groups, could improve the activity to a great extent. In
1996, Ojima et al. reported that such Taxol analogs, butitaxels, exhibited stronger
activity than paclitaxel. In combination with changes at C-10 acyl substitutions, 22