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Abstract

Bioassay guided fractionation of a crude extract of the marine sponge Neopetrosia exigua resulted in the first reported isolation of exiguamines A and B. These pyrroloquinone alkaloids have an unprecedented hexacyclic skeleton that has not been previously encountered in natural products. Biological studies have identified exiguamine A as a potent in vitro inhibitor of the enzyme indoleamine-2,3-dioxygenase (IDO). IDO is an enzyme expressed by tumor cells to evade the immune system. Inhibitors against this enzyme may allow the immune system to attack cancer cells, making this enzyme a potential drug target for anti-cancer agents. Investigation of the crude extract of a Bacillus sp. collected in Dominica led to the isolation of the known diketopiperazine cyclo(S-Val-S-Phe) (3.9). In vitro biological studies revealed that cyclo(S-Val-S-Phe) is able to promote neurite outgrowth, even in the presence of physiological inhibitors. In vivo studies have shown that cyclo(S-VaI-S-Phe) is able promote sprouting in serotonergic and adrenergic axons. Synthesis of the other three diastereomers led to the discovery that cyclo(R-Val-R-Phe) is also an in vitro activator of axonal outgrowth. Inhibitors of the G2 checkpoint are able to increase the cytotoxicity of DNA damaging chemotherapeutics. Bioassay guided fractionation of an extract of the South American plant Duguetia odorata led to the isolation of the G2 checkpoint abrogator, oliveroline. This investigation also led to the isolation of the previously unreported alkaloid N-methylguatterine, and the known alkaloids dehydrodiscretine and pseudopalmatine. Chemical investigation of the marine sponge Myrmekioderma granulatum led to the isolation of the new compounds abolenone and myrmekioside C, as well as the known compounds curcudiol, curcuphenol, abolene and sesquiterpenoid. Biological studies of these compounds revealed that curcudiol is a ligand of the sex hormone-binding globulin. This protein is involved in transporting and regulating the concentration of steroids such as testosterone and estradiol. Many pathological conditions have a lower plasma concentration of these steroids. Ligands to SHBG can release steroids into the blood, so this protein is a potential drug target to treat conditions where a hormone insufficiency is present.