Chaires J B, Leng F, Przewloka T, Fokt I, Ling Y H, Perez-Soler R, Priebe W
Department of Biochemistry, University of Mississippi Medical Center, Jackson 39216-4505, USA.
J Med Chem. 1997 Jan 31;40(3):261-6. doi: 10.1021/jm9607414.
A new bisintercalating anthracycline antibiotic, WP631, has been designed and synthesized. The rational design of the new compound was based upon the geometry of monomeric anthracyclines bound to DNA oligonucleotides observed in high-resolution crystal structures. Monomeric units of daunorubicin have been linked through their reactive 3' NH2 substituents on the daunosamine moieties to form the new bisanthracycline WP631. Viscosity studies confirmed that WP631 binds to DNA by bisintercalation. Differential scanning calorimetry and UV melting experiments were used to measure the ultratight binding of WP631 to DNA. The binding constant for the interaction of WP631 with herring sperm DNA was determined to be 2.7 x 10(11) M-1 at 20 degrees C. The large, favorable binding free energy of -15.3 kcal mol-1 was found to result from a large, negative enthalpic contribution of -30.2 kcal mol-1. A molecular model was generated that shows the favorable stereochemical fit of the linker in the DNA minor groove. The cytotoxicity of WP631 was compared to that of doxorubicin using MCF-7-sensitive and MCF-7/VP-16 MRP-mediated multidrug-resistant cell lines. These initial studies showed that while WP631 is slightly less cytotoxic than doxorubicin in the sensitive cell line, it appears to overcome MRP-mediated multidrug resistance and was much more cytotoxic against the MCF-7/VP-16 cell line than was doxorubicin. The design of new potential anticancer agents based on known structural principles was found to produce a compound with significantly increased DNA binding affinity and with interesting biological activity.
一种新型双插入蒽环类抗生素WP631已被设计并合成。该新型化合物的合理设计基于在高分辨率晶体结构中观察到的与DNA寡核苷酸结合的单体蒽环类药物的几何结构。柔红霉素的单体单元通过其柔红糖胺部分上具有反应活性的3' NH2取代基连接在一起，形成了新型双蒽环类药物WP631。黏度研究证实WP631通过双插入作用与DNA结合。差示扫描量热法和紫外熔解实验被用于测定WP631与DNA的超紧密结合。在20℃下，WP631与鲱鱼精DNA相互作用的结合常数被测定为2.7×10(11) M-1。发现-15.3 kcal mol-1的大的、有利的结合自由能是由-30.2 kcal mol-1的大的负焓贡献导致的。生成了一个分子模型，该模型显示了连接体在DNA小沟中的良好立体化学契合。使用MCF-7敏感细胞系和MCF-7/VP-16 MRP介导的多药耐药细胞系，将WP631的细胞毒性与阿霉素的细胞毒性进行了比较。这些初步研究表明，虽然WP631在敏感细胞系中的细胞毒性略低于阿霉素，但它似乎能克服MRP介导的多药耐药性，并且对MCF-7/VP-16细胞系的细胞毒性比阿霉素大得多。基于已知结构原理设计新的潜在抗癌药物，结果产生了一种DNA结合亲和力显著增加且具有有趣生物活性的化合物。
