Chemistry and Biology of Fascaplysin, a Potent Marine-Derived CDK-4 Inhibitor

Abstract

Marine natural products offer an abundant source of pharmacologically active agents with great diversity and complexity, and the potential to produce valuable therapeutic entities. Indole alkaloids is one of the important class of marine-derived secondary metabolites, with wide occurrence amongst variety of marine sources such as sponges, tunicates, algae, worms and microorganisms and have been extensively studied for their biological activities. Among this chemical family, a sponge-derived bis-indole alkaloid fascaplysin (1) exhibited broad range of bioactivities including antibacterial, antifungal, antiviral, anti-HIV-1-RTase, p56 tyrosine kinase inhibition, antimalarial, anti-angiogenic, antiproliferative activity against numerous cancer cell lines, specific inhibition of cyclin-dependent kinase-4 (IC(50) 350 nM) and action as a DNA intercalator. In the present review, the chemical diversity of natural as well as synthetic analogues of fascaplysin has been reviewed with a detailed account on synthetic reports and pharmacological studies. Our analysis of the structure-activity relationships of this family of compounds highlights the existence of various potential leads for the development of novel anticancer agents.

Triggering of Suicidal Erythrocyte Death by Fascaplysin

“…The marine sponge-derived bis-indole alkaloid Fascaplysin is effective against malaria [1], against bacterial, fungal, and viral infections [1], as well as against malignancy [1][2][3]. The efficacy against malignancy is at least in part due to activation of autophagy and apoptosis of tumor cells [2,3].…”

“…Fascaplysin further counteracts angiogenesis by triggering apoptosis of endothelial cells [4]. Cellular mechanisms involved include inhibition of p56 tyrosine kinase and of cyclin-dependent kinase-4 [1,4], DNA intercalation [1] as well as activation of caspases [2].…”

Marine Pharmaceuticals: A New Wave of Anti-angiogenic Drugs

“…It was later found to exert anti-proliferative activity against HeLa (ovarian cancer) cell line though apoptosis. Fascaplysin showed in vitro anti-angiogenic activity via vascular endothelial growth factor (VEGF) blockage, cell cycle arrest and apoptosis on human umbilical vein endothelial cells (HUVEC) [40]. It also showed selective inhibition of Cyclin-dependent kinase 4 (CDK4) and correspondingly arrested the cell cycle in the growth of multiple cancer cell types at the G0/1 phase.…”

Targeting Cellular Proapoptotic Agents from Marine Sources

“…and recent studies showed that fascaplysin is an inhibitor of Cdk4, with an IC 50 about 0.55 µM, and induce apoptosis in a variety of cancer cells [91]. Since decrease in the Cdk4 activity, fascaplysin has also been revealed to be capable of inhibiting angiogenesis [92].…”