STRUCTURE MODIFICATIONS AND THEIR INFLUENCES ON ANTITUMOR AND OTHER RELATED ACTIVITIES OF TAXOL AND ITS ANALOGS - Medicinal Chemistry of Bioactive Natural Products - page 111

3.4 NATURAL AND SEMISYNTHETIC TAXOIDS OVERCOMING
MULTIDRUG RESISTANCE (MDR)
MDR is one major reason for the failure of chemotherapy. 180 Overexpression of
P-glycoprotein (P-gP), which results in massive transport of anticancer drugs and
other hydrophobic substrates out of cells, is the best known contributing factor to
MDR. Also, other factors attributing to the failure of taxane anticancer drugs, such
as inherently insensitive isotypes of tubulin and amino acid mutations in tubulin,
will also be discussed in this section.
3.4.1 Structure-Modified Taxoids With Better Activity Toward
MDR Tumors
Although paclitaxel was reported to be effective against ovarian and breast cancers
resistant to other first-line anticancer drugs in clinics, the patients often relapsed
and did not respond to these antitumor agents, including paclitaxel, anymore.
Unfortunately, docetaxel was also inactive toward paclitaxel-resistant tumors.
In recent years, during research and development of new antitumor taxoids,
scientists have begun to shift their attention from begun drug-sensitive tumors to
drug-resistant tumors, especially paclitaxel-resistant tumors. It was found that
subtle changes in structure led to new taxoids with much more potent activities
against MDR tumors. It is worth noting that a series of taxoids with C-2, C-3 0 ,
and C-10 modifications prepared by Ojima's group can serve this purpose. It has
been reasoned that these taxoids are not good P-gP substrates and thus exhibited
potent activities against drug-resistant tumors.
In 1996, Ojima et al. reported that the introduction of carbonate and carbamate
to C-10 and the simultaneous replacement of 3 0 -phenyl with an alkenyl or alkyl
group provide the taxoids that exhibit one to two orders of magnitude higher
potency against drug-resistant cancer cells. 22 Among them, SB-T-1213 (109a)
was selected for additional research efforts because of highest potencies in this
series. Other paclitaxel analogs, IDN5109 (113)andABT-271(46), have shown their
efficacies against MDR tumors and have been subject to clinical evaluation as well.
Subsequently, new taxoids bearing 3 0 -cyclopropane and 3 0 -epoxide moieties
were synthesized. The R/S ratio (ratio of IC 50 in a drug-resistant cell to that in a
sensitive cell) was 2.48 for the 3 0 -cyclopropane/10-PrCO compound (8a). 23 Later
on, the same group discovered more potent analogs with modifications on the
C-2 as well as the C-3 0 and C-10 positions; three of them (109a-c) showed the
best R/S ratios at 0.89-1.3 in LCC6 (breast) and 0.92-1.2 in MCF-7 (breast) cell
lines, whereas for paclitaxel and docetaxel, 112 and 130 in LCC6 and 300 and 235
in MCF-7. 23 C-3 0 -difluoromethyl docetaxel analogs were found to be one to two
orders of magnitude more potent in MDR LCC6 cell lines. 27 Those C-3 0 -CF 2 H tax-
oids prepared from 14b-hydroxyl-10-DAB also exhibited comparable activity in
both normal and MDR cell lines, but they were generally less active than their coun-
terparts from 10-DAB. Several paclitaxel analogs bearing C-3 0 -(p-F)-substitution in
combination with 2-m-F, 2-difluoro, and 2-m-CF 3 -p-F benzoates were found to