抗癌药物阿克拉霉素-A的氧化还原代谢机理研究

大多数化疗药物因很强的毒副作用在临床应用中受到很大的限制，阿克拉霉素为蒽环药物家族新成员，因其抗癌活性高和毒副作用低在抗肿瘤药物中占有重要地位．本论文将药物置于代谢模型内，以光谱技术现场监测药物的代谢过程，研究了阿克拉霉素-A的氧化还原代谢机理．阿克拉霉素．A在体内的代谢过程为先通过一步二电子过程还原生成阿克拉氢醌．A，再脱去糖．其脱糖反应与介质的pH密切相关．脱糖、异构化后的产物7-去氧阿克拉霉醌经缔合后可生成双分子缔合物．整个代谢过程中并不产生半醌自由基，因而对心脏和细胞的毒性较小．研究结果同时也表明药物分子中的糖环结构与药物代谢及药物的毒副作用密切相关．研究成果有助于深入探讨药物的构效关系，对药物的临床应用有着重要的实际意义．

Study on the Redox Metabolism Mechanism of Aclacinomycin-A

Aclacinomycin, with high eutherapeuticity and low toxicity, is a new compound of anthacyclines, when the application of other anthracycline drugs in therapeutics is heavily restricted by their high toxicity. Up to now, it is still a question of antitumor action of ACM and its low toxicity. Antitumor activity, cardiotoxicity and cytotoxicity of these kinds of medicine are closely related to their redox behavior in vivo. In this work, an investigation of the redox mechanism of ACM-A in simulated metabolic process was made and a possible reduction mechanism of ACM-A was proposed: ACM-A is able to get two electrons becoming hydroaclarimycinone-A, then partly goes on a deaglycone to form 7-deoxyaclarimycinone in neutral and alkaline media. Two of 7-deoxyaclarimycinone can associate. As no semiquinone free radicals are produced in reduction and no free radical chain reaction exists to cause the damage of mitochondria DNA in heart and other cells, with low cardiotoxicity and cytotoxicity, ACM-A has wilder application in clinical. Another result obtained in this work is that the reduction of anthracycline drug and side effect in therapy was correlated to its aglycone structure. The results obtained offered new method for medical design and selection.