Twelve analogs of makaluvamines have been synthesized. These compounds were evaluated for their ability to inhibit the enzyme topoisomerase II. Five compounds were shown to inhibit topoisomerase catalytic activity comparable to two known topoisomerase II targeting control drugs, etoposide and m-AMSA. Their cytotoxicity against human colon cancer cell line HCT-116 and human breast cancer cell lines MCF-7 and MDA-MB-468 has been evaluated. Four makaluvamine analogs exhibited better IC50 values against HCT-116 as compared to control drug etoposide. One analog exhibited better IC50 value against HCT-116 as compared to m-AMSA. All 12 of the makaluvamine analogs exhibited better IC50 values against MCF-7 and MDA-MB-468 as compared to etoposide as well as m-AMSA. © 2007 Elsevier Ltd. All rights reserved.