Threadgill M D, Webb P, O'Neill P, Naylor M A, Stephens M A, Stratford I J, Cole S, Adams G E, Fielden E M
Medical Research Council Radiobiology Unit, Didcot, Oxfordshire, U.K.
J Med Chem. 1991 Jul;34(7):2112-20. doi: 10.1021/jm00111a029.
A series of 2- and 3-nitrothiophene-5-carboxamides bearing N-(omega-aminoalkyl) side chains has been prepared by treatment of the thiophenecarbonyl chloride with the appropriate (protected) omega-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-(dimethyl-amino)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.
通过用适当的（保护的）ω-氨基烷基胺处理噻吩甲酰氯，制备了一系列带有N-（ω-氨基烷基）侧链的2-和3-硝基噻吩-5-甲酰胺。通过相应的N-烯丙基酰胺的环氧化反应合成了类似的N-（环氧乙烷基甲基）硝基噻吩-5-甲酰胺。这两类化合物在体外均被评估为缺氧哺乳动物细胞的放射增敏剂以及选择性生物还原激活的细胞毒素。最有效的放射增敏剂是那些在侧链中具有强叔胺碱或环氧乙烷的试剂。体内研究表明，在给予0.34 mmol kg-1的小鼠中，2-甲基-N-[2-（二甲氨基）乙基]-3-硝基噻吩-5-甲酰胺对KHT肉瘤有轻微的放射增敏作用。然而，由于全身毒性，无法以更高剂量施用该化合物及相关叔胺。
