Dimers of Melampomagnolide B Exhibit Potent Anticancer Activity against Hematological and Solid Tumor Cells

Abstract

Novel carbamate (<b>7a</b>–<b>7h</b>) and carbonate (<b>7i</b>, <b>7j</b>, and <b>8</b>) dimers of melampomagnolide B have been synthesized by reaction of the melampomagnolide-B-triazole carbamate synthon <b>6</b> with various terminal diamino- and dihydroxyalkanes. Dimeric carbamate products <b>7b</b>,<b> 7c</b>, and <b>7f</b> exhibited potent growth inhibition (GI₅₀ = 0.16–0.99 μM) against the majority of cell lines in the NCI panel of 60 human hematological and solid tumor cell lines. Compound <b>7f</b> and <b>8</b> exhibited anticancer activity that was 300-fold and 1 × 10⁶-fold more cytotoxic than DMAPT, respectively, at a concentration of 10 μM against rat 9L-SF gliosarcoma cells. Compounds <b>7a</b>–<b>7j</b> and <b>8</b> were also screened against M9-ENL1 and acute myelogenous leukemia (AML) primary cell lines and exhibited 2- to 10-fold more potent antileukemic activity against M9-ENL1 cells (EC₅₀ = 0.57–2.90 μM) when compared to parthenolide (EC₅₀ = 6.0) and showed potent antileukemic activity against five primary AML cell lines (EC₅₀ = 0.76–7.3 μM)