Abstract

A series of 11 new substituted 1,5-dihydro-4,1-benzoxazepine derivatives was synthesised to study the influence of the methyl group in the 1-(benzenesulphonyl) moiety, the replacement of the purine by the benzotriazole bioisosteric analogue, and the introduction of a bulky substituent at position 6 of the purine, on the biological effects. Their inhibition against isolated HER2 was studied and the structure–activity relationships have been confirmed by molecular modelling studies. The most potent compound against isolated HER2 is 9a with an IC₅₀ of 7.31 µM. We have investigated the effects of the target compounds on cell proliferation. The most active compound (7c) against all the tumour cell lines studied (IC₅₀ 0.42–0.86 µM) does not produce any modification in the expression of pro-caspase 3, but increases the caspase 1 expression, and promotes pyroptosis.

摘要

合成了一系列 11 种新的取代的 1,5-二氢-4,1-苯并恶氮衍生物，以研究 1-(苯磺酰基) 部分中甲基的影响、苯并三唑生物等排类似物取代嘌呤的影响，以及在嘌呤的 6 位引入庞大的取代基，对生物效应的影响。研究了它们对分离的 HER2 的抑制作用，分子模型研究证实了结构-活性关系。对孤立的 HER2 最有效的化合物是9a，IC ₅₀为 7.31 µM。我们研究了目标化合物对细胞增殖的影响。对所有研究的肿瘤细胞系（IC ₅₀）最具活性的化合物（7c） 0.42–0.86 µM) 不会对 pro-caspase 3 的表达产生任何改变，但会增加 caspase 1 的表达，并促进细胞焦亡。