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．     

Interaction of Antitumor Drug Aclacinomycin‐A with DNA and Its Specific Sequence Site

Through UV and fluorescence spectrophotometries, the interaction of aclacinomycin‐A (ACM‐A) with DNA and its specific sequence have been investigated with the aid of circular dichroism spectrophotometry and differential pulse voltammetry method. The results demonstrated that ACM‐A was capable of intercalating DNA double helix, the π‐π electronic overlapping between π‐electrons of ACM‐A and base pair of DNA stabilized the ACM‐A‐DNA adduct, and through electrostatic interaction, the trisaccharide interacted with the minor groove of DNA owing to an amino group at C(3′). Electrochemical and spectroelectrochemical studies revealed that the original form of ACM‐A had higher affinity for DNA than the reduction form in which the trisaccharide group at C(7) was lost. According to the results obtained in this paper, ACM‐A showed preference for AT base pairs of the deoxyribonucleic acid duplex, and it was apt to interact with cytosine and thymine rather than the adenine of oligonucleotide.