jm0304764_si_001.pdf (29.91 kB)
Download fileSulfonyl-Containing Aldophosphamide Analogues as Novel Anticancer Prodrugs Targeted against Cyclophosphamide-Resistant Tumor Cell Lines
journal contribution
posted on 2004-07-15, 00:00 authored by Monish Jain, Junying Fan, Nesrine Z. Baturay, Chul-Hoon KwonA series of sulfonyl-group containing analogues of aldophosphamide (Aldo) were synthesized
as potential anticancer prodrugs that liberate the cytotoxic phosphoramide mustards (PM, IPM,
and tetrakis-PM) via β-elimination, a nonenzymatic activation mechanism. Kinetic studies
demonstrated that all these compounds spontaneously liberate phosphoramide mustards with
half-lives in the range of 0.08−15.2 h under model physiological conditions in 0.08 M phosphate
buffer at pH 7.4 and 37 °C. Analogous to Aldo, the rates of β-elimination in all compounds was
enhanced in reconstituted human plasma under same conditions. The compounds were more
potent than the corresponding phosphoramide mustards against V-79 Chinese hamster lung
fibroblasts in vitro (IC50 = 1.8−69.1 μM). Several compounds showed excellent in vivo antitumor
activity in CD2F1 mice against both P388/0 (Wild) and P388/CPA (CP-resistant) tumor cell
lines.