STRUCTURE MODIFICATIONS AND THEIR INFLUENCES ON ANTITUMOR AND OTHER RELATED ACTIVITIES OF TAXOL AND ITS ANALOGS - Medicinal Chemistry of Bioactive Natural Products - page 85

deacetyl baccatin 28c, presumably through transannular acyl migration in proximity,
Marder et al. attempted 53 to prepare 11,12-dihydropaclitaxel by attachment of the
C-13 side chain to 4-deacetyl-11,12-dihydrobaccatin 28a, which was prepared by
reduction of the 11,12 double bond with zinc and C-13 keto group with sodium
borohydride in baccatin 29, and then 4-acetylation. However, they found that the
docetaxel analogs from 28a were resistant to 4-acetylation, and the 4-deacetyl-
11,12-dihydrodocetaxel was almost inactive. Because of the poor activity of the
documented 4-deacetyl taxoids, it is not sure if the inactivity has developed from
the reduction of 11,12-olefin. Considering another report 48 (see Section 3.2.2.1), the
11,12-dihydropaclitaxel was indeed inactive even if 4-OH is acetylated.

3.2.2.3 14b and 1b Substitutions
From 14b-OH-10-DAB, a taxoid isolated from the needles of T. wallichiana Zucc.,
A-nor-seco baccatin 31 was derived from the oxidative cleavage of 14b-OH-10-DAB
30, and additional reduction of C-13 aldehyde with sodium cyanoborohydride and
incorporation of the side chain furnished A-seco paclitaxel and docetaxel analogs. 54,55
The C-13 ester A-nor-seco analogs 32 were 20-40 times weaker in activity, 54 and those
taxoids 33 (R 3 =H) with C-13 amide side chain almost inactive (more than three orders
of magnitudes weaker activity). The authors thus reasoned that it may have originated
from the mobility of C-13 amides. When the amide was methylated, the taxoids' 33
(R 3 =Me) activity were enhanced to be comparable with that of the esters. Based on
computer simulations, they found that this series of taxanes possessed convex confor-
mations similar to that of paclitaxel and docetaxel. Those with higher activity over-
lapped with hydrophobic clustering conformation of paclitaxel better than those
poorly active ones. Recently, Appendino et al. prepared more 14-nor-A-seco analogs,
all of which were almost inactive against MCF-7 cells. 56

OH

O

O

OH

OH

O

O

HO

H

HO O

HO H

O HO

OBz

AcO

BzO

AcO

31

30

O

O

O O

NH O NH O

R 1

R

OH

OH

R 2 N O

Ph O O

OH

OH

R 3

H

H

O

O

HO HO

OBz

OBz

OAc

OAc

33

32

The SAR results for many other 14b-OH paclitaxel and docetaxel analogs were
scattered in different parts in Section 3.2, for example, the results in Refs. 20, 54,