Synthesis of a series of nitrothiophenes with basic or electrophilic substituents and evaluation as radiosensitizers and as bioreductively activated cytotoxins

Article abstract of DOI:10.1021/jm00111a029

A series of 2- and 3-nitrothiophene-5-carboxamides bearing N-(ω-aminoalkyl) side chains has been prepared by treatment of the thiophenecarbonyl chloride with the appropriate (protected) ω-aminoalkylamine. Analogous N-(oxiranylmethyl)nitrothiophene-5-carboxamides have been synthesized by epoxidation of the corresponding N-allylamide. Compounds in both classes were evaluated in vitro both as radiosensitizers of hypoxic mammalian cells and as selective bioreductively activated cytotoxins. The most potent radiosensitizers were those agents with strong tertiary amine bases or oxiranes in the side chain. Studies in vivo showed that 2-methyl-N-[2-(dimethylamino)ethyl]-3-nitrothiophene-5-carboxamide caused slight radiosensitization of the KHT sarcoma in mice given 0.34 mmol kg^-1. However, administration of this and related tertiary amines at higher doses was precluded by systemic toxicity.