Saha Mouli, Das Saurabh
Department of Chemistry (Inorganic Section), Jadavpur University, Kolkata, 700032, India.
Heliyon. 2021 Aug 11;7(8):e07746. doi: 10.1016/j.heliyon.2021.e07746. eCollection 2021 Aug.
Cytotoxicity by anthracycline antibiotics is attributed to several pathways. Important among them are formation of free-radical intermediates. However, their generation makes anthracyclines cardiotoxic which is a concern on their use as anticancer agents. Hence, any change in redox behavior that address cardiotoxicity is welcome. Modulation of redox behavior raises the fear that cytotoxicity could be compromised. Regarding the generation of free radical intermediates on anthracyclines, a lot depends on the surrounding environment (oxic or anoxic), polarity and pH of the medium. In case of anthracyclines, one-electron reduction to semiquinone or two-electron reduction to quinone-dianion are crucial both for cytotoxicity and for cardiotoxic side effects. The disproportion-comproportionation equilibria at play between quinone-dianion, free quinone and semiquinone control biological activity. Whatever is the form of reduction, semiquinones are generated as a consequence of the presence of anthracyclines and these interact with a biological target. Alizarin, a simpler anthracycline analogue and its Mn complex were subjected to electrochemical reduction to realize what happens when anthracyclines are reduced by compounds present in cells as members of the electron transport chain. Glassy carbon electrode maintained at the pre-determined reduction potential of a compound was used for reduction of the compounds. Nucleobases and calf thymus DNA that were maintained in immediate vicinity of such radical generation were used as biological targets. Changes due to the generated species under aerated/de-aerated conditions on nucleobases and on DNA helps one to realize the process by which alizarin and its Mn complex might affect DNA. The study reveals alizarin was more effective on nucleobases than the complex in the free radical pathway. Difference in damage caused by alizarin and the Mn complex on DNA is comparatively less than that observed on nucleobases; the complex makes up for any inefficacy in the free radical pathway by its other attributes.
蒽环类抗生素的细胞毒性归因于多种途径。其中重要的是自由基中间体的形成。然而，它们的产生使蒽环类药物具有心脏毒性，这是其作为抗癌药物使用时的一个问题。因此，任何解决心脏毒性的氧化还原行为变化都是值得欢迎的。氧化还原行为的调节引发了细胞毒性可能受损的担忧。关于蒽环类药物上自由基中间体的产生，很大程度上取决于周围环境（有氧或无氧）、介质的极性和pH值。对于蒽环类药物来说，单电子还原为半醌或双电子还原为醌二价阴离子对于细胞毒性和心脏毒性副作用都至关重要。醌二价阴离子、游离醌和半醌之间的歧化 - 逆歧化平衡控制着生物活性。无论还原形式如何，半醌是蒽环类药物存在的结果，并且这些半醌与生物靶点相互作用。茜素是一种更简单的蒽环类类似物及其锰配合物，进行了电化学还原，以了解当蒽环类药物被细胞中作为电子传递链成员的化合物还原时会发生什么。将玻碳电极维持在化合物的预定还原电位用于化合物的还原。将保持在这种自由基产生紧邻区域的核碱基和小牛胸腺DNA用作生物靶点。在通气/除气条件下，所产生的物质对核碱基和DNA的影响有助于人们了解茜素及其锰配合物可能影响DNA的过程。研究表明，在自由基途径中，茜素对核碱基的作用比配合物更有效。茜素和锰配合物对DNA造成的损伤差异相对小于在核碱基上观察到的差异；该配合物通过其其他特性弥补了自由基途径中的任何无效性。
