STRUCTURE MODIFICATIONS AND THEIR INFLUENCES ON ANTITUMOR AND OTHER RELATED ACTIVITIES OF TAXOL AND ITS ANALOGS - Medicinal Chemistry of Bioactive Natural Products - page 119

Scientists from BMS applied the disulfide linkage to the preparation of several
prodrugs of paclitaxel, containing glucose, GSH, or captopril. Under reductive acti-
vation conditions, the captopril conjugate was most stable in vitro and exhibited
the most enhanced activity (50 times). More importantly, a 60% tumor regression
rate against L2987 lung carcinoma mice model was observed at a 125-mg/kg
dose for the compound, whereas no activity occurred for paclitaxel at its MTD
of 30 mg/kg. 226
Contrary to the usual preparation of hydrophilic conjugates, Ali et al. prepared a
series of hydrophobic a-bromoacyl prodrugs of paclitaxel with 6, 8, 10, 12, 14, and
16 carbon chains 227 on the basis of their discovery that the association of paclitaxel
prodrugs with lipid bilayers was influenced by the chain length of the bromoacyl
paclitaxel analogs. 228 In the absence of a-bromo substitution, the prodrugs were 50-
to 250-fold less active, which implies the assistance of bromine in the hydrolysis
of 2 0 -carbonate. Interestingly, it was found that the longer the chain, the stronger the
growth inhibitory activity, probably developing ''the slow hydrolysis of the prodrug
followed by sustained delivery of paclitaxel to the tumor,'' according to the

authors.
Non-prodrug water-soluble paclitaxel analogs were also reported. 79 Because
their C-10 positions were covalently attached to secondary amines instead of acet-
ate in paclitaxel, they cannot convert into paclitaxel under physiological conditions.

3.5.2 Prodrugs Designed for Enhancing Specificity

Antibody-directed enzyme prodrug therapy (ADEPT) is one promising strategy in
prodrug design. In this strategy, the conjugate consisted of a monoclonal antibody
of a tumor cell surface receptor for recognition and the prodrug of an antitumor
agent subjected to specifically enzymatic cleavage to release the drug at the
tumor site. Rodrigues et al. 229 reported for the first time the application of the
ADEPT method to paclitaxel, using the conjugate of b-lactamase and MAb, and
the cephalosporin-paclitaxel prodrug. As an improvement to this brilliant strategy,
BMS scientists changed the structures of linkers and antibodies to ensure a faster
release, more stable to unspecific hydrolysis and specificity of prodrug activation.
The 3,3-dimethyl-4-aminobutyric acid linked conjugate demonstrated the fastest
release of paclitaxel, and its specificity was also observed as expected when acti-
vated by the melanotrasferrin mAb-fused protein L-49-sFv-b-lactamase in human
3677 melanoma cells. 230 To avoid immunogenicity caused by the non-human
enzyme, glucuronidase was chosen as the enzyme in ADEPT. 231 Unfortunately,
although the prodrug was hydrolyzed by glucoronidase to exhibit similar cytotoxi-
city to paclitaxel, activation of the prodrug with enzyme-MAb was not realized
after 24 hours probably because of an insufficient amount of enzyme bound to
cells. Schmidt et al. prepared another ADEPT candidate in 2001. 232 They chose
2 0 -carbamate instead of 2 0 -esters, and the para-nitro group on the benzene ring in
the linker can facilitate the attack of the phenol ion to 2 0 -carbamate to liberate the
parental drug. However, this prodrug may also suffer from similar problems
because 100 mg/mL of enzyme was needed for fast release of the parental drug.