STRUCTURE MODIFICATIONS AND THEIR INFLUENCES ON ANTITUMOR AND OTHER RELATED ACTIVITIES OF TAXOL AND ITS ANALOGS - Medicinal Chemistry of Bioactive Natural Products - page 114

Some macrocyclic taxoids such as 99b and 99c were among the most potent
inhibitors for drug-resistant cancer cells. 147
Dimers of paclitaxel or docetaxel with 2-deacetoxytaxinine J were designed and
prepared for their dual role in cytotoxicity as well as MDR reversal activity,
because 2-deacetoxytaxinine J exhibited strong MDR reversal activity. However,
biological evaluation results are disappointing. 183
Interestingly, some conjugates of paclitaxel and camptothecin through amino
acid and imine linkage exhibited better R/S ratios against drug-resistant tumor cells
induced by the two drugs, KB-CPT and 1A9-PTX10. 153

3.4.2 Nonpaclitaxel-Type Taxoids With MDR Reversal Activities

Some naturally occurring or semisynthetic non-Taxol taxoids can restore MDR
tumor cells sensitivity toward paclitaxel and other anticancer drugs. These taxoids
are usually weakly cytotoxic; thus, they are ideal candidates for combined use with
cytotoxic agents.
Ojima et al. prepared 23 taxoids with hydrophobic side chains at different posi-
tions of 10-DAB. 184 Taxoids with mono-hydrophobic ester substitution could be
grouped into two categories. One group including taxoids with C-7 and C-10 mod-
ifications showed strong reversal activity ( > 95%) in most cases at the concentration
of 1 3 mM, and another group with C-13 and C-2 modifications exhibited less or no
activity. The effects of introducing two or three hydrophobic groups seemed to be
complicated. Baccatin III-7-(trans-1-naphthanyl-acrylic acid) ester (115) is the best
among those semisynthetic taxoids, which does not increase paclitaxel accumula-
tion in sensitive tumor cell MCF-7, but it drastically increases the paclitaxel accu-
mulation in drug-resistant cell MCF-7-R with overexpression of P-gP.
Kobayashi et al. first reported the effects of nonpaclitaxel-type taxoids from
Taxus cuspidata on vincristine (VCR) accumulation in the adriamycin-resistant
human leukemia K562/ADM cell. 185 Seven taxoids belonging to different subtypes
are as potent as Verapamil for MDR reversal, and some of them can competitively
bind to P-gP. Among them, taxinine (105) and taxuspine C (117) were chosen for
additional studies. 186-189 For taxinine, hydrophobic groups attached to C-2, C-5, and
C-13 enhance MDR reversal activity, and to C-9 and C-10 reduce the activity. 187
A hydrogenated product (116) of taxinine retaining 4(20)-exomethylene is the
most potent MDR-reversal taxoid reported to date. 181 Deacylations at C-2, 5, 9,
and 10 in taxuspine C result in a drastic reduction of activity. 189 Two taxoids
2-deacetyl taxinine and 1-hydorxy Taxuspine C were isolated from T. cuspidata,
both of which showed better activity than Verapamil in vitro. 190 A common obser-
vation for taxinine and taxuspine C derivatives is that a phenyl containing hydro-
phobic group attached to C-5 apparently increases the accumulation of paclitaxel in
MDR. However, comparison of these results with those obtained from baccatin III
derivatives is difficult because of reversed C-5 configuration.
In 2002, Kobaysahi et al. reviewed their work on taxoids, including MDR rever-
sal and other biological activities of these taxoids. 191 Interested readers can refer to
it for a comprehensive description.