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Marine natural products : synthesis and isolation of bioactive analogues

University of British Columbia

Tauramamide (2-12), a linear acylpentapeptide recently isolated from cultures of Brevibacillus laterosporus (PNG-276) collected in Papua New Guinea, was synthesized in 9 steps and 29% overall yield. Besides confirming the proposed structure, synthetic (2-12) allowed the antimicrobial assessment of this novel antibiotic. Additionally, a new analogue of the surfactin depsipeptides family named dealkylsurfactin (2-48), was prepared in 10 steps and 14% overall yield. The compound was employed as a biological tool in binding studies between the mitotic regulator isomerase Pinl and the microtubule-associated protein tau, a crucial interaction involved in Alzheimer's disease. Chemical exploration of Garveia annulata, a seasonal hydroid collected in Barkley Sound, British Columbia, led to the isolation of twelve secondary metabolites including four new compounds (3-53 to 3-56). Nine of these metabolites showed inhibition of indoleamine 2,3- dioxigenase (IDO), with the annulins among the most potent in vitro IDO inhibitors isolated to date. IDO plays a central role in immune escape, which prevents the immunological rejection of tumors or the allogeneic fetus. The ceratamine inspired antimitotic agent (4-142) and inactive analogue (4-157) were synthesized in no more than 8 steps, with overall yields of 20% and 15% respectively. Activity evaluation of these analogues suggested that potency improves with planarity and that the synthetically laborious imidazo[4,5,d]azepine core heterocycle of ceratamines is not required for activity. Haplosamate A (5-62), isolated from the marine sponge Dasychalina fragilis collected in Papua New Guinea, was found to be the first member of a new family of cannabinoid-active sterols. Saturation transfer double-difference (STDD) NMR experiments confirmed that (5-62)specifically binds the cannabinoid human receptors CB1 and CB2 via the classical cannabinoid pharmacophore. A growing appreciation of the therapeutic potential of PI3K inhibitors has encouraged the development of new inhibitory compounds with enhanced potency, selectivity and pharmacological properties. Such substances are destined to the treatment of inflammatory and autoimmune disorders as well as cancer and cardiovascular diseases. An optimization program intended to develop more stable and isoform-selective PI3K inhibitors based on the marinederived natural product liphagal (6-1), led to the preparation of a small library of synthetic analogues.

Thesis/Dissertation

application/pdf

2008-12-03

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/7526

Chemistry

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/