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首页> 外文期刊>Anti-Cancer Drug Design >5-substituted analogues of 3-hydroxymethyl-5-aziridinyl-1-methyl-2-(1H-indole-4,7-dione)prop-2-en- 1-ol (EO9, NSC 382459) and their regioisomers as hypoxia-selective agents: structure-cytotoxicity in vitro.
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5-substituted analogues of 3-hydroxymethyl-5-aziridinyl-1-methyl-2-(1H-indole-4,7-dione)prop-2-en- 1-ol (EO9, NSC 382459) and their regioisomers as hypoxia-selective agents: structure-cytotoxicity in vitro.

机译：3-羟甲基-5-氮丙啶基-1-甲基-2-（1H-吲哚-4,7-二酮）丙-2-烯-1-醇的5-取代类似物（EO9，NSC 382459）和它们的区域异构体-选择剂：体外结构细胞毒性。

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摘要

A series of regioisomeric analogues of 3-hydroxymethyl-5-aziridinyl-1-methyl-2-[1H-indole-4,7-dione]prop-2-en-1 -ol (EO9, NSC 382459) with the hydroxymethyl and hydroxypropenyl substituents situated at either the 2- or the 3-position of the indole ring were synthesized. The compound lacking the 2-hydroxypropenyl substituent (31) had similar properties to EO9 under both aerobic and hypoxic conditions against V79 cells and was more potent against a human tumour cell line (A549) than EO9. It was reduced by human DT-diaphorase (DTD) at more than double the rate of EO9, thus implicating the importance of the enzyme activation step. Compound 16 (lacking the 3-hydroxymethyl substituent) was a better substrate for human DTD than EO9, yet exhibited lesser toxicity under both aerobic and hypoxic conditions. The toxicity generated by 16 was attributed to the 5-aziridinyl moiety and suggests a greater contribution from the 3-substituent over the 2-substituent. The toxicity of EO9 was attributed to a combination of the aziridinyl group and the leaving group properties of the 3-hydroxymethyl substituent. In general, compounds with a 5-methylaziridinyl moiety, such as EO8, exhibited substantially better hypoxia-selectivity due to much slower reduction by DTD (20-fold), thus reducing aerobic potency. All compounds had similar electron affinities, as indicated by their one-electron reduction potentials.
机译：一系列3-羟甲基-5-氮丙啶基-1-甲基-2- [1H-吲哚-4,7-二酮] prop-2-en-1-ol（EO9，NSC 382459）的区域异构体与羟甲基和合成了位于吲哚环的2-或3-位的羟基丙烯基取代基。缺少2-羟基丙烯基取代基（31）的化合物在有氧和低氧条件下对V79细胞具有与EO9相似的特性，并且比EO9对人肿瘤细胞系（A549）更有效。人DT-心肌黄递酶（DTD）将其还原的速率是EO9的两倍以上，因此暗示了酶激活步骤的重要性。化合物16（缺少3-羟甲基取代基）是人DTD的较好底物，而不是EO9，但在有氧和低氧条件下均显示出较小的毒性。 16产生的毒性归因于5-叠氮基基团部分，表明3-取代基比2-取代基有更大的贡献。 EO9的毒性归因于氮丙啶基和3-羟甲基取代基的离去基团的结合。通常，具有5-甲基叠氮基部分的化合物，例如EO8，由于DTD的还原速度要慢得多（20倍），因此具有更好的缺氧选择性，从而降低了有氧能力。所有化合物具有相似的电子亲和力，如其单电子还原电位所示。

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