Departments of Chemistry and Earth & Ocean Sciences, University of British Columbia, Vancouver, BC, Canada V6T 1Z1.
J Med Chem. 2010 Nov 11;53(21):7843-51. doi: 10.1021/jm101012q.
Desbromoceratamine A (3) exhibits significantly less potent activity than the natural product ceratamine A (1) in a cell-based assay for antimitotic activity. Synthesis of the ceratamine A analogue 4 has shown that replacing the bromine atoms in the natural product with methyl groups generates an analogue that is more active than natural ceratamine A (1). Further enhancement of the antimitotic activity of the ceratamine pharmacophore has been achieved in the synthetic analogue 33, which has both bromine atoms replaced with methyl groups and an additional methyl substituent on the amino nitrogen at C-2. An efficient synthetic route has been developed to 33 that should enable the first in vivo evaluation of the new ceratamine microtubule-stabilizing pharmacophore and has provided several additional analogues for structure-activity relationship evaluation.
Desbromoceratamine A（3）在基于细胞的抗有丝分裂活性测定中比天然产物 ceratamine A（1）的活性低得多。Ceratamine A 类似物 4 的合成表明，用甲基取代天然产物中的溴原子会产生比天然 ceratamine A（1）更具活性的类似物。在合成类似物 33 中，通过进一步增强 ceratamine 药效团的抗有丝分裂活性，已经实现了这一目标，该类似物的两个溴原子均被甲基取代，并且在 C-2 位的氨基氮上增加了一个额外的甲基取代基。已经开发出一种有效的合成路线来合成 33，这应该能够首次对新型 ceratamine 微管稳定药效团进行体内评价，并提供了几种其他类似物用于结构-活性关系评估。
