Nicolaou K C, Scarpelli R, Bollbuck B, Werschkun B, Pereira M M, Wartmann M, Altmann K H, Zaharevitz D, Gussio R, Giannakakou P
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Chem Biol. 2000 Aug;7(8):593-9. doi: 10.1016/s1074-5521(00)00006-5.
Numerous analogs of the antitumor agents epothilones A and B have been synthesized in search of better pharmacological profiles. Insights into the structure-activity relationships within the epothilone family are still needed and more potent and selective analogs of these compounds are in demand, both as biological tools and as chemotherapeutic agents, especially against drug-resistant tumors.
A series of pyridine epothilone B analogs were designed, synthesized and screened. The synthesized compounds exhibited varying degrees of tubulin polymerization and cytotoxicity properties against a number of human cancer cell lines depending on the location of the nitrogen atom and the methyl substituent within the pyridine nucleus.
The biological screening results in this study established the importance of the nitrogen atom at the ortho position as well as the beneficial effect of a methyl substituent at the 4- or 5-position of the pyridine ring. Two pyridine epothilone B analogs (i.e. compounds 3 and 4) possessing higher potencies against drug-resistant tumor cells than epothilone B, the most powerful of the naturally occurring epothilones, were identified.
为了寻找更好的药理特性，已合成了许多抗肿瘤药物埃坡霉素A和B的类似物。仍需要深入了解埃坡霉素家族内的构效关系，并且需要更有效和更具选择性的这些化合物类似物，作为生物学工具和化疗药物，特别是用于对抗耐药肿瘤。
设计、合成并筛选了一系列吡啶埃坡霉素B类似物。根据吡啶核内氮原子和甲基取代基的位置，合成的化合物对多种人类癌细胞系表现出不同程度的微管蛋白聚合和细胞毒性特性。
本研究中的生物学筛选结果确定了邻位氮原子的重要性以及吡啶环4位或5位甲基取代基的有益作用。鉴定出两种吡啶埃坡霉素B类似物（即化合物3和4），它们对耐药肿瘤细胞的效力高于天然存在的最强效埃坡霉素埃坡霉素B。
