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Biologically active secondary metabolites isolated from marine and terrestrial sources

University of British Columbia

A series of new and known secondary metabolites were isolated from marine and terrestrial sources guided by two newly developed, cell-based assays. Investigations into the antimitotic properties of a crude extract from the Caribbean octocoral Erythropodium caribaeorum resulted in the isolation and identification of the known antimitotic agent eleutherobin (61) and six novel structural analogues, 69-74. E. caribaeorum proved to be a new and abundant source of eleutherobin (61), whose pre-clinical development had been impeded by its scarcity, and the structural variations of the new diterpenoids offered key insights into proposed pharmacophore models for microtubule-stabilizing compounds. In addition, single crystal X-ray diffraction analysis and NOE difference experiments provided the first solid-state and solution conformations for eleutherobin (61) and may aid in the development of new models for microtubule stabilization. [diagram] The crude extract from a marine sponge, Stylissa flabelliformis, exhibited potent activity in a new bioassay for G2 cell cycle checkpoint inhibitors. Bioassay-guided fractionation of this active extract resulted in the isolation and identification of the natural product [diagram] debromohymenialdisine (91) and three related alkaloids (85, 94, 103). These compounds were the first G2 checkpoint inhibitors to be found by a rational screen and were structurally distinct from previously reported G2 checkpoint inhibitors. In addition, debromohymenialdisine (91) was found to specifically act on the protein kinases Chkl and Chk2, thus providing a new biochemical tool to probe the molecular basis of G2 checkpoint inhibition. [diagram] As a result of a large-scale screen of natural extracts for G2 checkpoint inhibitors, a series of a-pyrones from the Taiwanese tree Cryptocarya concinna were found to exhibit potent inhibitory activity. Bioassay-guided purification resulted in the isolation and identification of the natural product cryptofolione (130) and three related polyketide lactones (148, 131, 138). Synthetic modifications on these metabolites yielded four additional analogues and led to mode of action and structure-activity relationship studies. The G2 checkpoint inhibitors isolated from C. concinna were structurally different from previously known inhibitors and appear to act by a novel mechanism of action. [diagram]

Thesis/Dissertation

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2009-10-07

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http://hdl.handle.net/2429/13670

Chemistry

University of British Columbia

UBCV

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