Nitro seco analogues of the duocarmycins containing sulfonate leaving groups as hypoxia-activated prodrugs for cancer therapy

Journal of Medicinal Chemistry
Ralph J StevensonAmir Ashoorzadeh

Abstract

The synthesis of 19 (5-nitro-2,3-dihydro-1H-benzo[e]indol-1-yl)methyl sulfonate prodrugs containing sulfonate leaving groups and 7-substituted electron-withdrawing groups is reported. These were designed to undergo hypoxia-selective metabolism to form potent DNA minor groove-alkylating agents. Analogues 17 and 24, containing the benzyl sulfonate leaving group and a neutral DNA minor groove-binding side chain, displayed hypoxic cytotoxicity ratios (HCRs) of >1000 in HT29 human cancer cells in vitro in an antiproliferative assay. Four analogues maintained large HCRs across a panel of eight human cancer cell lines. In a clonogenic assay, 19 showed an HCR of 4090 in HT29 cells. Ten soluble phosphate preprodrugs were also prepared and evaluated in vivo, alone and in combination with radiation in SiHa human tumor xenografts at a nontoxic dose. Compounds 34 and 39 displayed hypoxic log(10) cell kills (LCKs) of 1.78 and 2.71, respectively, equivalent or superior activity to previously reported chloride or bromide analogues, thus showing outstanding promise as hypoxia-activated prodrugs.

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Jul 20, 2011·Bioorganic & Medicinal Chemistry·Amir AshoorzadehRalph J Stevenson

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Citations

May 20, 2016·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Teng LiuJun Lin
Aug 5, 2014·Chembiochem : a European Journal of Chemical Biology·Moana TercelSonia M Alix
Dec 12, 2012·Chemistry : a European Journal·Lutz F TietzeIngrid Schuberth
Nov 24, 2018·Current Drug Targets·Min-Xia SuJin-Jian Lu
Apr 28, 2018·Journal of Materials Chemistry. B, Materials for Biology and Medicine·Mingxing HuYongmei Xie
Dec 24, 2018·Chemical Society Reviews·Amit SharmaJong Seung Kim

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