Studies On The Metabolic Mechanisms Of Antitumor Antibiotics And Their Interactions With DNA By Spectroelectrochemistry

Anthracycline antibiotics, such as doxorubicin and daunorubicin, are some of the most commonly used anticancer agents today, mainly attribute to their broad spectrum of activity versus human cancers. Although the exact mechanism of action is still somewhat unclear, there are several proposed mechanisms, incliuding intercalating DNA duplexes and stabilizing topoisomerase II-mediated-double-stranded DNA breaks. And DNA, as the foremost material element of life, plays an indispensable role either during the growing and developing of life form or its diseases and consenescence. Therefore, the investigations of the metabolic mechanisms of antitumor antibiotics and their interactions with DNA will provide a reliable evidence and reasonable explanation for pharmacological and medical research.As a novel technique, Spectroelectrochemistry is an effective tool to study the metabolic process of drugs in vivo. Combined of electrochemistry and in situ spectrophotometry, it is convenient to establish the redox metabolic model in vitro and to supervise the changes of the drugs and their target molecules simultaneously.Adopting Spectroelectrochemistry techniques, the present work is mainly concerned with the metabolic mechanisms of antitumor antibiotic aclacinomycin and its interaction with DNA in comparison with several effective clinical drugs, such as daunorubicin, epirubicin and idarubicin. These results have provided useful insights into DNA conformation and drug- DNA interactions. In particular, it partly direct the discovery of derivatives or methodology which will maximize tumor response and minimize side effect, especially the acute cardiotoxicity.Study on the Redox Mechanism of Aclacinomycin-AAclacinomycin(ACM), with high therapeuticity and low toxicity, is a newcompound of anthracycline antibiotics, when the application of other anthracycline drugs in therapeutics is heavily restricted by their high toxicity. It has demonstrated distinct activity against both leukemias and solid tumors. Up to now, the exact mechanism of action of ACM is still somewhat unclear, though the antitumor activity, cardiotoxicity and cytotoxicity of these kinds of antibiotics 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 is made and a possible reduction mechanism of ACM-A is proposed.ACM-A is able to get two electrons to become 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 exist to cause the damage of mitochondria DNA in heart and other cells, ACM-A has wilder application in clinical for its low cardiotoxicity and cytotoxicity. Another result obtained in this work is the reduction of anthracycline drug and side effect in therapy are correlated to its sugar structure. The results can offer new method for medical design and clinical application.Study on the interaction of ACM-A with DNA by spectroelectrochemistryOn the grounds of UV-spectrophotometry and fluorescence spectrophotometry, the interaction of aclacinomycin (ACM) -A and its specific sequence sites of DNA have been investigated, with the aids of circular dichroism spectrophotometry and Differential Pulse Voltammetry methods. The results demonstrate that ACM-A is capable of intercalating between the base pairs of DNA double helix, the π-π electronic overlapping between π -electron of ACM-A and DNA stablizes the ACM-DNA adduct, and through electrostatic interaction the sugar ring interacts with the minor groove of DNA. The binding constant of ACM-A with lambdaDNA is 4.22 X 10 L.mol-1 . As the results obtained in this paper, ACM-A shows preference for AT base pairs of the deoxyribonucleic acid duplex. In the presence of oligonucleotide, ACM-A interacts with DNA in the order: poly (C) >poly (T)> poly (A), with itsC(4)-OH, C(6)-OH and C(5) =O in aglycone moie...