STRUCTURE MODIFICATIONS AND THEIR INFLUENCES ON ANTITUMOR AND OTHER RELATED ACTIVITIES OF TAXOL AND ITS ANALOGS - Medicinal Chemistry of Bioactive Natural Products - page 88

Bz Bz

RO

RO

O

NH OH

NH O

O OH

OH

Ph O

Ph O

OH OH

HO

HO

O

O

BzO

AcO

AcO

BzO

39a R=Ac
39b R=H

40a R=Ac
40b R=H

O

OH

Bz

NH

O OH

Ph O

OH

HO

O

AcO

BzO

41

Walker et al. 67 prepared 10a-spiro epoxide (42a) and its 7-methoxymethyl (MOM)
ether (42b), which exhibited comparable cytotoxicity and tubulin assembly activity
with paclitaxel.
10-Deoxygenation was realized by either Barton's method 68,69 or samarium
iodide-mediated deoxygenation. 70,71 The latter one is direct and chemoselective,
and function group protection is not needed. Treatment of paclitaxel with SmI 2
led to the formation of 10-deacetoxy product 43a in 5 minutes, which was reduced
to 10-deacetoxy-9b-OH paclitaxel 43b with prolonged treatment of SmI 2 . For
10-deacetyl paclitaxel, 9b-OH derivatives 43b and 43c were obtained in a ratio
of 50:40. All taxoids were biologically evaluated, and two of them, 10-deacetoxy
and 9b-OH-10-deacetylpaclitaxel, were comparable with paclitaxel, whereas the
other is less active in tubulin assembly and cytotoxicity assays. 68,72,73

O

Bz R 1

O

O Bz

NH

R 2

OR

NH O

OH

Ph O

Ph O

OH

OH

HO

H

O

BzO HO

H

AcO O

BzO

OAc

42a R=H
42b R=CH 2 OCH 3

43a R 1 =H, R 2 =O
43b R 1 =H, R 2 = β− OH

43c R 1 =OH, R 2 = β− OH

3.2.3.2 C-9 Substitutions
When the C-9 keto group in paclitaxel was replaced by hydroxyl, either a or b-OH
analogs displayed slightly higher potencies. The 9a-OH, that is, 9(R)-OH, analog of