Revisiting Bromohexitols as a Novel Class of Microenvironment-Activated Prodrugs for Cancer Therapy.,ChemMedChem

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Revisiting Bromohexitols as a Novel Class of Microenvironment-Activated Prodrugs for Cancer Therapy.
ChemMedChem ( IF 3.6 ) Pub Date : 2019-11-26 , DOI: 10.1002/cmdc.201900578
Henrik Johansson ₁ , Omar Hussain ₂ , Simon J Allison ₂ , Tony V Robinson ₁ , Roger M Phillips ₂ , Daniel Sejer Pedersen ₁

Affiliation

Bromohexitols represent a potent class of DNA-alkylating carbohydrate chemotherapeutics that has been largely ignored over the last decades due to safety concerns. The limited structure-activity relationship data available reveals significant changes in cytotoxicity with even subtle changes in stereochemistry. However, no attempts have been made to improve the therapeutic window by rational drug design or by using a prodrug approach to exploit differences between tumour physiology and healthy tissue, such as acidic extracellular pH and hypoxia. Herein, we report the photochemical synthesis of highly substituted endoperoxides as key precursors for dibromohexitol derivatives and investigate their use as microenvironment-activated prodrugs for targeting cancer cells. One endoperoxide was identified to have a marked increased activity under hypoxic and low pH conditions, indicating that endoperoxides may serve as microenvironment-activated prodrugs.

中文翻译：

回顾溴己糖醇作为一类新型的微环境激活的前药用于癌症治疗。

溴己糖醇代表着一类有效的DNA烷基化碳水化合物化学治疗方法，由于安全方面的考虑，在过去的几十年中，溴化己糖醇一直被人们忽略。可用的有限的结构-活性关系数据揭示了细胞毒性的显着变化，甚至立体化学上的细微变化。但是，尚未尝试通过合理的药物设计或通过使用前药方法来改善肿瘤生理学与健康组织之间的差异（例如酸性细胞外pH和低氧）来改善治疗范围。在这里，我们报告了高度取代的内过氧化物作为二溴己糖醇衍生物的关键前体的光化学合成，并研究了它们作为靶向癌细胞的微环境激活的前药的用途。

更新日期：2019-11-27

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