Mechanistic study of O-methylcedrelopsin and dehydrogeijerin

Plants that can survive in the harsh environment of South Texas have the potential to produce molecules with activity against diverse biological targets. The Mountain torchwood, Amyris madrensis, was evaluated because the crude lipophilic extract had potent activity against prostate cancer cells. Multiple cytotoxic compounds were isolated using bioassay guided fractionation including 14 previously identified coumarins. Two coumarins, O-methylcedrelopsin and dehydrogeijerin, were evaluated for antiproliferative activities against cancer cell lines. O-methylcedrelopsin has an IC₅₀ of 7.8 and 27.8µM in HeLa and PC-3 cells respectively. Dehydrogeijerin also showed activity in the low micromolar range with an IC₅₀ of 16.0µM in HeLa cells and 43.0µM in PC-3 cells. Both O-methylcedrelopsin and dehydrogeijerin caused a dose dependent accumulation of cells in G₂/M as determined by flow cytometry. They have no effects on interphase microtubule structures or on the assembly of purified tubulin, suggesting a mechanism different from microtubule binding compounds. The compounds do however initiate the formation of abnormal mitotic spindles which closely resemble those formed following treatment of cells with mitotic kinase inhibitors. The hypothesis that O-methylcedrelopsin and dehydrogeijerin target mitotic kinases, specifically polo like kinase 1 (PLK1) or cyclin dependent kinase 1 (CDK1) is being tested. Two structurally similar coumarins, 7-O-prenylscopoletin and cedrelopsin, were also identified but they have 10-fold lower antiproliferative potency. These structures will be informative in defining the moieties optimal for inhibiting mitotic progression. Supported by NIDCR (COSTAR) DE14318 and DoD W81XWH-08–1-0395.