Sulfonyl-containing aldophosphamide analogues as novel anticancer prodrugs targeted against cyclophosphamide-resistant tumor cell lines

Journal of Medicinal Chemistry
Monish JainChul-Hoon Kwon

Abstract

A 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 beta-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 degrees C. Analogous to Aldo, the rates of beta-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 (IC(50) = 1.8-69.1 microM). Several compounds showed excellent in vivo antitumor activity in CD2F1 mice against both P388/0 (Wild) and P388/CPA (CP-resistant) tumor cell lines.

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Citations

Jan 25, 2013·Therapeutic Delivery·Margaret S Landis
Jan 6, 2007·Organic & Biomolecular Chemistry·Chuanzheng ZhouJyoti Chattopadhyaya
Jun 18, 2019·Drug Metabolism Reviews·Himanshu VermaOm Silakari
Aug 26, 2020·Expert Opinion on Drug Metabolism & Toxicology·Gabriel TaoRomi Ghose
Jul 30, 2021·Recent Patents on Anti-cancer Drug Discovery·Pranav GuptaZhe-Sheng Chen

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