Kruse L I, Ladd D L, Harrsch P B, McCabe F L, Mong S M, Faucette L, Johnson R
Department of Medicinal Chemistry, Smith Kline & French Laboratories, Swedeland, Pennsylvania 19406.
J Med Chem. 1989 Feb;32(2):409-17. doi: 10.1021/jm00122a020.
In an attempt to identify a soluble oncodazole analogue that could be easily formulated, a series of substituted oncodazoles was synthesized and evaluated for tubulin binding affinity, in vitro cytotoxicity against cultured mouse B-16 cells, and ability to prolong lifespan at the maximally tolerated dose in the P388 mouse leukemia model. Biological evaluation of all the isomeric methyloncodazoles demonstrated the thiophene 4'-position to be the only site of significant bulk tolerance, although substitution of this position with polar or charged functional groups abolished biological activity. Simple esters of the 4'-carboxymethyloncodazole were shown to have enhanced antitumor activity and tubulin binding affinity relative to oncodazole. Despite a failure of this study to identify a water-soluble oncodazole with antitumor activity, the structure-activity relationship developed led to a derivative with enhanced activity in the P388 leukemia model and facilitated the preparation of a biologically active photolabile analogue.
为了鉴定一种易于配制的可溶性癌抑散类似物，合成了一系列取代的癌抑散，并对其进行了微管蛋白结合亲和力、对培养的小鼠B-16细胞的体外细胞毒性以及在P388小鼠白血病模型中最大耐受剂量下延长生存期的能力评估。所有异构甲基癌抑散的生物学评估表明，噻吩4'-位是唯一具有显著体积耐受性的位点，尽管用极性或带电荷的官能团取代该位点会消除生物活性。结果表明，4'-羧甲基癌抑散的简单酯相对于癌抑散具有增强的抗肿瘤活性和微管蛋白结合亲和力。尽管这项研究未能鉴定出具有抗肿瘤活性的水溶性癌抑散，但所建立的构效关系导致了一种在P388白血病模型中活性增强的衍生物，并有助于制备具有生物活性的光不稳定类似物。
