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

Novel carbamate (7a-7h) and carbonate (7i, 7j, and 8) dimers of melampomagnolide B have been synthesized by reaction of the melampomagnolide-B-triazole carbamate synthon 6 with various terminal diamino- and dihydroxyalkanes. Dimeric carbamate products 7b, 7c, and 7f exhibited potent growth inhibition (GI(50) = 0.16-0.99 mu M) against the majority of cell lines in the NCI panel of 60 human hematological and solid tumor cell lines. Compound 7f and 8 exhibited anticancer activity that was 300-fold and 1 x 10(6)-fold more cytotoxic that DMAPT, respectively, at a concentration of 10 mu M against rat 9L-SF gliosarcoma cells. Compounds 7a-7j and 8 were also screened against M9-ENL1 and acute myelogeous leukemia (AML) primary cell lines and exhibited 2- to 10-fold more potent antileukemic activity against M9-ENL1 cells (EC50 = 0.57-2.90 mu M) when compared to parthenolide (EC50 = 6.0) and showed potent antileukemic activity against five primary AML cell lines (EC50 = 0.76-7.3 mu M).