Cera C, Palumbo M
Department of Pharmaceutical Sciences, University of Padova, Italy.
Nucleic Acids Res. 1991 Oct 25;19(20):5707-11. doi: 10.1093/nar/19.20.5707.
The thermodynamic parameters governing the interaction of 4'-deoxy,4'-iododoxorubicin (4'-IAM) to double stranded DNA or 175 bp nucleosomes have been evaluated at different ionic strength and temperature conditions by means of fluorescence techniques. The iodo-anthracycline exhibits quite different characteristics from the parent compounds adriamycin (AM) and daunomycin (DM) and other second generation derivatives. In fact, the contribution of electrostatic interactions to the total free energy of binding is rather poor and the changes in enthalpy, usually high and negative, are low and eventually positive. Unlike other members of its family, 4'-IAM exhibits preference for the nucleosomal structure. In addition, its binding to isolated DNA is remarkably cooperative. Circular dichroism studies show changes in the geometry of the intercalation complex when the drug binds to nucleosomes. The possibility for the iodo-sugar moiety to act as an alkylating or free-radical producing species was also considered as an alternative mechanism of action. However, no evidence was obtained to support these hypotheses. Thus the major differences observed in DNA-binding in comparison to parent anthracyclines appear to be mostly related to the lower pKa and higher lipophilicity exhibited by 4'-IAM.
通过荧光技术,已在不同离子强度和温度条件下评估了4'-脱氧、4'-碘柔红霉素(4'-IAM)与双链DNA或175 bp核小体相互作用的热力学参数。碘代蒽环类药物表现出与母体化合物阿霉素(AM)、柔红霉素(DM)及其他第二代衍生物截然不同的特性。事实上,静电相互作用对结合总自由能的贡献相当小,焓变通常较高且为负值,而此处焓变较低且最终为正值。与该家族的其他成员不同,4'-IAM对核小体结构表现出偏好。此外,它与分离的DNA结合具有显著的协同性。圆二色性研究表明,当药物与核小体结合时,插入复合物的几何结构会发生变化。碘糖部分作为烷基化剂或自由基产生剂发挥作用的可能性也被视为一种替代作用机制。然而,未获得支持这些假设的证据。因此,与母体蒽环类药物相比,在DNA结合方面观察到的主要差异似乎大多与4'-IAM较低的pKa和较高的亲脂性有关。