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UBC Theses and Dissertations

Bioactive marine natural products : isolation, structure elucidation and synthesis of pharmacophore analogues Carr, Gavin


Bioassay-guided fractionation of the marine sponge Spongia irregularis led to the isolation of a new sulfated sesterterpenoid, irregularasulfate (2.16), along with two known sulfated sesterterpenoids, halisulfate 7 (2.14) and hipposulfate C (2.15). All three compounds (2.14-2.16) inhibit the related phosphatases calcineurin, PP1 and PP2A. The analogue 2.23 was synthesized and showed similar phosphatase inhibitory activity to the natural products. One new bafilomycin analogue, bafilomycin F (3.2), along with three known bafilomycin analogues, bafilomycin A1 (3.1), bafilomycin B1 (3.3) and bafilomycin D (3.4), were isolated from a marine-derived bacterium identified as Streptomyces sp. All four compounds (3.1-3.4) are extremely potent inhibitors of autophagy. Indoleamine 2,3-dioxygenase (IDO) is a relatively new and promising cancer drug target. Synthetic analogues of exiguamine A, the most potent IDO inhibitor reported to date, were prepared and evaluated for their ability to inhibit IDO in vitro and in vivo. The most potent of these analogues (4.32, 4.38, 4.39, 4.43 and 4.52) inhibit IDO in vitro with potency comparable to exiguamine A. A new exiguamine analogue, exiguamine C (5.2), was isolated from the crude extract of Neopetrosia exigua. Exiguamine B (5.1) was also isolated from this crude extract in order to confirm the structure, and the relative configuration was determined with the aid of synthetic exiguamine B. Bioassay-guided fractionation of the marine fungus Plectosphaerella cucumerina led to the isolation of three new alkaloids, plectosphaeroic acids A-C (6.1-6.3). All three compounds inhibit IDO with approximately the same potency, while the related compound T988 A was completely inactive. Cinnabarinic acid was synthesized in order to aid with the structure elucidation of plectosphaeroic acids A-C. Cinnabarinic acid and analogues were also active against IDO and represent a new pharmacophore for IDO inhibition. The depsipeptides turnagainolide A (7.3) and turnagainolide B (7.4) were isolated from Bacillus sp. Both of these compounds activate the enzyme SHIP1 in vitro. Total syntheses of turnagainolides A and B were accomplished using solid-phase peptide synthesis, and comparison of the synthetic material with the natural products confirmed their structures. Two novel compounds, the peptide 8.1 and the carotenoid 8.7, were isolated from two unidentified marine sponges. The structure of 8.1 was confirmed by a total synthesis using solid-phase peptide synthesis. Analogues of 8.1 were also prepared and showed moderate cytotoxicty against T98G cancer cells.

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