Antiproliferative and cytotoxic effects of newly discovered halogenated coral prostanoids from the Japanese stolonifer Clavularia viridis on human myeloid leukemia cells in culture.

The antiproliferative and cytotoxic activities of newly discovered halogenated coral prostanoids (chlorovulone, bromovulone, and iodovulone) from the Japanese stolonifer Clavularia viridis and their related compounds were determined in HL-60 cells in culture. The order of antiproliferative and cytotoxic activities of naturally occurring marine prostanoids against HL-60 cells was chlorovulone I greater than bromovulone I = iodovulone I greater than clavulone I or II greater than prostaglandin A2. The IC50 (concentrations required to inhibit cell growth by 50%) value (0.03 microM (0.01 microgram/ml)) and cytotoxic effects (greater than 0.3 microM (0.1 microgram/ml)) of chlorovulone I were about 200 and 100 times stronger than those of prostaglandin A2, respectively, on the molar basis. From our data on the structure-activity relationship of the halogenated coral prostanoids and the related compounds, we elucidated that 1) the alkylidencyclopentenone structure in these prostanoids was essential for the antiproliferative and cytotoxic activities against HL-60 cells and the introduction of halogen function at C-10 position in the structure enhanced the activities (C1 = F greater than Br = I greater than H); 2) the stereospecificity of the 12-hydroxyl group in the chlorovulone molecule was not required for the activities; 3) the presence of dienone (C5-6 and C7-8) in the structure potentiated the activities. Bivariate DNA/bromodeoxyuridine analysis with a flow cytometer showed that chlorovulone I transiently arrested the cell cycle progression from G1 to S after 24-hr exposure to the nontoxic concentrations (0.03 and 0.09 microM) and caused the lasting blockade of leukemia cells in G1 at the cytotoxic concentration. These results suggest that these coral prostanoids and related compounds may be a promising antileukemic agent.