Synthesis and discovery of lipopeptides from marine sources as sodium channel blockers for the treatment of prostate cancer

The genetic and biochemical diversity of marine microorganisms makes them a promising source of useful pharmaceutical agents. The marine cyanobacterium Lyngbya majuscula produces a large number of lipopeptides that are ligands for the voltage-gated sodium channel (VGSC). Compounds that block sodium channel current are known to be effective as anticonvulsants, anesthetics, and anti-arrthymic drugs. In addition, the expression of VGSC's was found to correlate with the metastatic potential of prostate cancer cells, indicating that sodium channel blockers could have therapeutic use as prostate cancer drugs. The jamaicamides are lipopeptides isolated from L. majuscula that exhibit sodium channel blocking activity at 5 muM. They share a common pharmacophore with the hermitamides, another class of lipopeptides isolated from the same cyanobacterium. The hermitamides are structurally less complex than the jamaicamides but have not been tested for sodium channel activity. Herein, we report the enantioselective synthesis of the hermitamides, their sodium channel activity, and effects on prostate cancer cell proliferation. We also report the enantioselective synthesis of jamaicamide C carboxylic acid.;Additional work is reported targeting the dimerization interface of core binding factor (CBF), a protein implicated in the development of acute myelogenous leukemia (AML). A lead compound was designed using computational screening, NMR spectroscopy and x-ray crystallography. A large series of analogues was synthesized and tested for their ability to inhibit dimerization. We have identified several analogues that potently bind to CBF, inhibit dimerization and block proliferation of AML leukemia cell lines.