Angiogenesis, the formation of new blood capillaries from preexisting blood vessels, is a vital process in growth of solid tumors and development to malignant stage. This makes angiogenesis a desirable target for cancer treatment. In this work, design and syntheses of structurally simplified analogues of cortistatin A (1), a novel antiangiogenic steroidal alkaloid from Indonesian marine sponge, and their biological activities were investigated. One of the analogues, 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 in vivo antiangiogenic activity and significant antitumor effect by oral administration.