Biakamides A–D, Unique Polyketides from a Marine Sponge, Act as Selective Growth Inhibitors of Tumor Cells Adapted to Nutrient Starvation

Biakamides A–D, novel unusually unique polyketides, were isolated from an Indonesian marine sponge (<i>Petrosaspongia</i> sp.) with a constructed bioassay using PANC-1 human pancreatic cancer cells. Through detailed analyses of the one- and two-dimensional NMR spectra of biakamides, planar chemical structures possessing a terminal thiazole, two <i>N</i>-methyl amides, a chloromethylene, and a substituted butyryl moiety were obtained. After elucidation of the configuration of the secondary alcohol moiety in biakamides A and B, the absolute stereostructures of the two secondary methyl groups in biakamides A–D were determined by the asymmetric total syntheses of all possible stereoisomers from the optically pure monoprotected 2,4-dimethyl-1,5-diol. Biakamides A–D showed selective antiproliferative activities against PANC-1 cells cultured under glucose-deficient conditions in a concentration-dependent manner. The primary mode of action of biakamides was found to be inhibition of complex I in the mitochondrial electron transport chain

Creation of Readily Accessible and Orally Active Analogue of Cortistatin A

Syntheses of structurally simplified analogues of cortistatin A (<b>1</b>), a novel antiangiogenic steroidal alkaloid from Indonesian marine sponge, and their biological activities were investigated. The analogues were designed by considering the 3-D structure of <b>1</b>. Compound <b>30</b>, in which the isoquinoline moiety was appended to the planar tetracyclic core structure, showed potent antiproliferative activity against human umbilical vein endothelial cells (HUVECs) together with high selectivity and also showed <i>in vivo</i> antiangiogenic activity and significant antitumor effect by oral administration