STRUCTURE MODIFICATIONS AND THEIR INFLUENCES ON ANTITUMOR AND OTHER RELATED ACTIVITIES OF TAXOL AND ITS ANALOGS - Medicinal Chemistry of Bioactive Natural Products - page 121

distributed proteases or esterases in vivo. These prodrugs are nontoxic, maybe the
least toxic paclitaxel prodrugs hitherto reported. They did release the parental
drug upon treatment of human plasmin, although at relatively high concentrations
(100 mg/mL of plasmin and 200 mM of prodrug).
Considering the reductive condition in the anaerobic environment in the center
of tumor tissue, Damen et al. designed and prepared 2 0 -carbonate and 3 0 -N-carbamate
prodrugs of paclitaxel that release the parental drug targeting hypoxic tumor tissue.
Two of 11 prodrugs are selected for additional investigation. 242
In 2004, Liu et al. made an effort to incorporate estradiol into C-2 0 , 7, and 10
positions in Taxol to target the drug to estrogen receptor (ER) positive breast
cancer. For C-2 0 and C-7 conjugates, no satisfactory results were obtained for either
activity or selectivity. But a 7-epi-10-conjugated taxoid (119) did exhibit some
selectivity between ER-positive and negative cancer cells, and ER-b (MDA-MB-
231 cell) and ER-a expressing (MCF-7) cancer cells. 243

OH

OO

HO

O

O

Bz

O

NH O

OH

Ph O

OH

HO

H

O

AcO

BzO

119

3.6 OTHER BIOLOGICAL ACTIONS OF PACLITAXEL

Apoptosis is another important mechanism for cell poisoning, in addition to tubulin
assembly promotion and microtubule stabilization for paclitaxel, especially at a
high concentration (sub mMtomM level). It is also observed that in higher concen-
trations (5 to 50 mM), paclitaxel induced tumor necrosis through microtubules
rather than apoptosis. 244

Note that paclitaxel concentration in the clinic is lower

than mM.
The involvement of many biochemical pathways and cytokines in paclitaxel-
induced apoptosis has been extensively investigated. Among them, bcl-2, the
well-known apoptosis inhibitor, was found to be phosphorylated in the presence
of paclitaxel, with its inhibitory effect on apoptosis downregulated. One phosphor-
ylation position is Ser-70, and the cells with Ser70 to Ala mutant showed lower
reponse to paclitaxel-induced apoptosis. Deletion of the bcl-2 loop area comprising