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 IC50 values of 2.3 μM, 1.8 μM, and 2.8 μM, respectively. 4-Methyl, 4-chloro, and 3,4-methylenedioxy derivatives showed the best activity against MCF-7 among the phenethyl analogs with IC50 values of 2.3 μM, 2.8 μM, and 2.4 μM, 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 Log GI50 values were shown by the fluorobenzyl analog against the renal cancer cell line RXF-393 (<-8.0 M) and dimethoxy phenethyl analog against the CNS cancer cell line, SF-268 (<-8.0 M). The best Log LC50 value was shown by the fluorobenzyl analog against the breast cancer cell line MCF-7 (-6.01 M). © 2007 Elsevier Ltd. All rights reserved.