Chemistry Reference
In-Depth Information
A group from Daiichi Co. reported many 9b-dihydro-paclitaxel and docetaxel
analogs, including 47,
77
49,
78
and 50a-b,
81
which exhibited significant antitumor
effects in vitro and in vivo against MDR tumors. Some of them were also highly
water soluble as well as orally active.
Distefano et al. reported the activity of 7,9-pyrazoline (general formula 111) and
C-seco (general formula 112) analogs. The pyrazoline analogs of docetaxel were
better than paclitaxel but less active than docetaxel against adariamycin-resistant
MCF-7 cells.
181
C-seco analogs were less potent than pyrazoline analogs. Because
these pyrazoline analogs could arrest a cell cycle at G
2
/M phase and DNA fragmen-
tation, their activities are probably related to apoptosis.
An interesting finding on taxoid-related MDR is that the inactivity of orally
administered paclitaxel originated from overexpressing P-gP in the gastrointestinal
tract. Combined use of paclitaxel and a P-gP inhibitor will improve bioavailability
to a great extent. Taxoid 113 was found to be a poor substrate of P-gP, which thus
showed good oral bioavailability (48% p.o./i.v.) and significant efficacy in clinical
trial.
58
10-Deoxy-10-C-morpholinoethyl deocetaxel analogs are also orally active
taxoids, and 10-(C-morpholinoethyl)-7-MeO docetaxel (114) is the best in this
series.
80
O
R
2
O
OH
R
2
NH
O
N
OH
NH
O
NH
R
1
O
R
1
O
OH
OH
HO
H
O
HO
BzO
H
O
AcO
BzO
AcO
112
111
O
HO
N
Boc
O
NH
O
OH
Boc
O
NH
O
O
OMe
OH
Ph
O
O
O
H
O
OH
AcO
BzO
HO
H
O
O
BzO
AcO
113
114
DJ-927 (49), a 9-dihydro-7-deoxy docetaxel analog under its phase I clinical
trial, was effective against various tumors, especially P-gP overexpressing MDR
tumors in vivo. Additional investigation showed that it is not a P-gP substrate
and its cytotoxicity is not influenced by P-gP modulators. Although the authors pro-
posed that the effectiveness of DJ-927 may be partly from higher intracellular accu-
mulation, its mechanism against MDR tumors should be addressed in the future.
182
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