Graduate Thesis Or Dissertation
 

Biologically active cyclic depsipeptides from marine cyanobacteria

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https://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/w3763873b

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  • This thesis describes the chemical investigation of marine cyanobacteria collected in Madagascar and Panama with an emphasis on the isolation and structure elucidation of medicinally relevant secondary metabolites. A collection of the marine cyanobacterium Lyngbya majuscula from the Radames Islands, Madagascar yielded two new cyclic depsipeptides, radamamides A and B, and the previously reported compound antanapeptin A. The planar structures of these compounds were established by NMR spectroscopic analysis. All three despsipeptides contain C₈ alkynoate moieties. A stereoselective synthesis of the four stereoisomers of 3-hydroxy-2-methyl-7-octynoic acid (Hmoya) was undertaken to ascertain the absolute configuration of this residue in radamamide B and antanapeptin A. Radamamide A displayed some anti-malarial activity relative to artemisinin (99% and 65% at 10 μM and 1 μM, respectively). A potent antiproliferative depsipeptide was discovered in collaboration with the Panama International Cooperative Biodiversity Groups Project (ICBG), which focuses on drug discovery, biodiversity conservation and sustainable economic growth. This cyanobacterial depsipeptide named coibamide A, in tribute to its discovery from UNESCO world heritage site Coiba National Park, was isolated from a filamentous Leptolyngbya sp. of marine cyanobacterium. The planar structure of coibamide A was elucidated by exhaustive 1D and 2D NMR spectroscopy (including natural abundance ¹⁵N and variable temperature experiments) in combination with mass spectrometry (TOF-ESI-MS[superscript]n and FT-MS[superscript]n experiments). This highly methylated, cyclic depsipeptide exhibited an unprecedented selectivity profile in the NCI 60 cancer cell line panel and appears to act via a novel mechanism. Three new cyclic depsipeptides were isolated from the same Panamanian Leptolyngbya sp. which produced the antiproliferative metabolite, coibamide A. The planar structures of leptolyngolides A and B were established using an extensive array of 1D and 2D NMR experiments, including HSQC, HSQC-TOCSY and HMBC. The molecular structure of a minor compound, leptolyngolide C was inferred from 1D NMR and mass spectrometric data. These cyanobacterial metabolites contain the β-amino-hydroxy acid residue, 3-amino-2-hydroxy-7-octynoic acid (AMO). All three compounds displayed moderate biological activity against a range of tropical diseases.
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file details Rebecca_A._Medina_PhD_Thesis.pdf 2017-08-01 Público Descargar