Portugal José, Cashman Derek J, Trent John O, Ferrer-Miralles Neus, Przewloka Teresa, Fokt Izabela, Priebe Waldemar, Chaires Jonathan B
Instituto de Biologia Molecular de Barcelona, CSIC, Parc Científic de Barcelona, Josep Samitier, 1-5, E-08028, Barcelona, Spain.
J Med Chem. 2005 Dec 29;48(26):8209-19. doi: 10.1021/jm050902g.
A new bisintercalating anthracycline (WP762) has been designed, in which monomeric units of daunorubicin have been linked through their amino groups on the daunosamine moieties using an m-xylenyl linker. Differential scanning calorimetry and UV melting experiments were used to measure the ultratight binding of WP762 to DNA. The binding constant for the interaction of WP762 with herring sperm DNA was determined to be 7.3 (+/-0.2) x 10(12) M(-1) at 20 degrees C. The large favorable binding free energy of -17.3 kcal mol(-1) was found to result from a large negative enthalpic contribution of -33.8 kcal mol(-1) and an opposing entropic term (-TDeltaS = +16.5 kcal mol(-1)). A comparative molecular modeling study rationalized the increased binding by the m-xylenyl linker of WP762 positioning in the DNA minor groove compared to the p-xylenyl linker found in WP631, the first bis-anthracycline of this type. The cytotoxicity of WP762 was compared to that of other anthracyclines in Jurkat T lymphocytes. These studies, together with an analysis of the cell-cycle traverse in the presence of WP762, suggest that in these cells the new drug is more cytotoxic than the structurally related WP631.
一种新型双嵌入蒽环类药物（WP762）已被设计出来，其中柔红霉素的单体单元通过其柔红糖胺部分上的氨基使用间二甲苯基连接子相连。差示扫描量热法和紫外熔解实验被用于测量WP762与DNA的超紧密结合。在20℃时，WP762与鲱鱼精DNA相互作用的结合常数被测定为7.3（±0.2）×10¹² M⁻¹。发现大的有利结合自由能-17.3 kcal mol⁻¹是由大的负焓贡献-33.8 kcal mol⁻¹和相反的熵项（-TΔS = +16.5 kcal mol⁻¹）导致的。一项比较分子模拟研究解释了与WP631（此类第一种双蒽环类药物）中发现的对二甲苯基连接子相比，WP762的间二甲苯基连接子定位在DNA小沟中导致结合增加的原因。在Jurkat T淋巴细胞中，将WP762的细胞毒性与其他蒽环类药物的细胞毒性进行了比较。这些研究，连同对WP762存在时细胞周期进程的分析，表明在这些细胞中，这种新药比结构相关的WP631更具细胞毒性。
