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.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:BVAU.2429/3960 |
| Date | 11 1900 |
| Creators | Brastianos, Harry Charilaos |
| Publisher | University of British Columbia |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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