Shinkre Bidhan A, Raisch Kevin P, Fan Liming, Velu Sadanandan E
Department of Chemistry, University of Alabama at Birmingham, 901 14th Street South, Birmingham, AL 35294, USA.
Bioorg Med Chem. 2008 Mar 1;16(5):2541-9. doi: 10.1016/j.bmc.2007.11.051. Epub 2007 Nov 28.
Analogs of marine alkaloid, makaluvamine, bearing substituted benzyl and substituted phenethyl side chains have been synthesized and their antiproliferative activities have been evaluated. 4-Methyl, 4-chloro, and 4-fluoro substituted benzyl analogs possessed pronounced antiproliferative effects on the breast cancer cell line, MCF-7 at IC(50) values of 2.3 microM, 1.8 microM, and 2.8 microM, respectively. 4-Methyl, 4-chloro, and 3,4-methylenedioxy derivatives showed the best activity against MCF-7 among the phenethyl analogs with IC(50) values of 2.3 microM, 2.8 microM, and 2.4muM, respectively. In general, methoxy substitutions resulted in slight loss in activity in both benzyl and phenethyl series. Benzyl, 4-fluorobenzyl, 3,4-dimethoxyphenethyl, and 3,4-methylenedioxyphenethyl analogs were tested by NCI in their 60 cell lines in vitro human cancer cell screen. All four compounds showed excellent inhibition against several tested cancer cell lines. Benzyl and 4-fluorobenzyl analogs were relatively more active than 3,4-dimethoxy phenethyl and 3,4-methylenedioxy phenethyl analogs. In NCI assays, the best LogGI(50) values were shown by the fluorobenzyl analog against the renal cancer cell line RXF-393 (<-8.0M) and dimethoxy phenethyl analog against the CNS cancer cell line, SF-268 (<-8.0M). The best LogLC(50) value was shown by the fluorobenzyl analog against the breast cancer cell line MCF-7 (-6.01 M).
已合成了带有取代苄基和取代苯乙基侧链的海洋生物碱马卡鲁胺类似物，并评估了它们的抗增殖活性。4-甲基、4-氯和4-氟取代的苄基类似物对乳腺癌细胞系MCF-7具有显著的抗增殖作用，IC(50)值分别为2.3 microM、1.8 microM和2.8 microM。在苯乙基类似物中，4-甲基、4-氯和3,4-亚甲二氧基衍生物对MCF-7的活性最佳，IC(50)值分别为2.3 microM、2.8 microM和2.4 microM。一般来说，甲氧基取代导致苄基和苯乙基系列的活性略有损失。苄基、4-氟苄基、3,4-二甲氧基苯乙基和3,4-亚甲二氧基苯乙基类似物在NCI的60种人癌细胞系体外筛选中进行了测试。所有四种化合物对几种测试的癌细胞系均显示出优异的抑制作用。苄基和4-氟苄基类似物比3,4-二甲氧基苯乙基和3,4-亚甲二氧基苯乙基类似物相对更具活性。在NCI测定中，氟苄基类似物对肾癌细胞系RXF-393显示出最佳的LogGI(50)值（<-8.0M），二甲氧基苯乙基类似物对中枢神经系统癌细胞系SF-268显示出最佳的LogGI(50)值（<-8.0M）。氟苄基类似物对乳腺癌细胞系MCF-7显示出最佳的LogLC(50)值（-6.01 M）。
