STRUCTURE MODIFICATIONS AND THEIR INFLUENCES ON ANTITUMOR AND OTHER RELATED ACTIVITIES OF TAXOL AND ITS ANALOGS - Medicinal Chemistry of Bioactive Natural Products - page 117

3.5 DESIGN, SYNTHESIS, AND PHARMACOLOGICAL ACTIVITY
OF PRODRUGS OF PACLITAXEL
Currently the paclitaxel formulation contains a surfactant, Cremophor EL, to
improve the poor water solubility of the drug. Some adverse effects including
hypersensitivity have been attributed to Cremophor. Other severe adverse effects,
such as neutropenia and dose-dependent neurotoxicity, also occur at a high dosage
of paclitaxel administration. Improved water solubility may lower the dosage of
paclitaxel because of effective transportation of the drug to the active sites,
which thus reduces high dosage-related toxicity. Several alternative formulations,
such as emulsions 206 and liposomes 207,208 have been developed to improve efficacy
and minimize the toxicity of paclitaxel. Another approach, design and preparation
of water-soluble prodrugs will be discussed here. Also, the ''smart'' prodrugs aimed
at specific sites or kinds of tumors have emerged recently. Some prodrugs with both
improved water solubility and enhanced effectiveness and specificity were also
documented.
3.5.1 Prodrugs Prepared to Improve Water Solubility
Most water-soluble prodrugs were realized by the derivatization of 2 0 -OH and 7-OH
positions, the two most liable positions in paclitaxel. Some prodrugs are as active as
the parental drug both in vitro and in vivo.
a-amino acids have been applied to the preparation of water-soluble taxanes as
early as the late 1980s. A series of amino acids was conjugated to 2 0 -OH through a
glutaryl linker, and the asparagine- and glutamine-glutarylpaclitaxels improved the
water solubility as much as three orders of magnitude. 209 These two derivatives as
well as serine- and glycine-derivatives showed strong cytotoxicity against several
sensitive cancer cell lines, and no activity against paclitaxel-resistant cells.
Poly(L-glutamic acid)-paclitaxel (PG-TXL), 210,211 a derivative about five orders
of magnitude more soluble than paclitaxel, was active against several kinds of
tumors in vivo, including those not responsive to both paclitaxel and a combination
of paclitaxel and polyglutamic acid.
Hydroxy acid esters were also applied to the synthesis of prodrugs. Damen
et al. 212 prepared 2 0 - and 7-malic esters of paclitaxel and found that 2 0 -ester behaved
as the prodrug, whereas 7-ester and 2 0 , 7-diesters did not. The 2 0 -malyl paclitaxel
and its sodium salt are more water soluble than paclitaxel by 20 and 60 times, and
both are stable at pH 7.4 PBS buffer for 48 hours at 37 C. The prodrug, because of
its two-fold higher maximum tolerance dose (MTD) than its parent drug, exhibited
more significant antitumor activity at a higher dosage. Niethammer et al. reported a
7-glycerolyl carbonate of paclitaxel as a prodrug with improved antitumor activity
and hydrophilicity. 213 The prodrug, with 50-fold higher solubility in water, pos-
sessed 2.5-fold higher MTD, reduced toxicity to stem cells by 100 times, and exhib-
ited almost equal activity in vitro as compared with paclitaxel. In vivo results are
also promising—tumor growth regression in all prodrug treating groups (40 mg/kg)
were greater than that in paclitaxel groups (16 mg/kg). A series of polyol-carbonate