UBC Theses and Dissertations

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UBC Theses and Dissertations

Synthesis of biologically active marine natural product analogues Nodwell, Matthew B.

Abstract

Natural products have long been a source of inspiration for many drugs in human use. The Andersen lab examines compounds from marine sources that can be used as lead structures for drug discovery. Synthetic studies, structure-activity relationships (SAR) and biological findings of two such compounds are described in this thesis. The first is pelorol, a meroterpene isolated from a tropical sponge Dactylospongia elegans. Pelorol is a small molecule activator of SHIP 1, a phosphatase that is a negative regulator of the P13K pathway in hematopoetic cells. Using a synthetic route from a previous co-worker, Lu Yang, a series of SHIP 1 activating compounds based on pelorol were synthesized. These compounds were evaluated for selectivity, potency, and efficacy in a series of biological studies, leading to the discovery of 2.27 as a preclinical lead compound. Water-soluble prodrugs of the SHIP 1-activating compounds were also synthesized and their properties reported. The second compound examined is ceratamine A, an alkaloid isolated from the sponge Pseudoceratina sp. from Papua New Guinea. Ceratamines A and B are microtubule stabilizing antimitotic agents that may be useful in cancer chemotherapy. The core imidazo[4,5,d]azepine heterocycle of the ceratamines has no precedent among known synthetic or natural compounds. The relatively simple structure of the ceratamines and the novel antimitotic phenotype they generate makes them attractive targets. Desbromo ceratamine A (3.44) was synthesized by an efficient and scaleable route, confirming the structure of ceratamine A and validating the biological activity of the core pharmacophore. Synthetic efforts towards ceratamine A were ultimately thwarted by the inability to install the bromine atoms present in the natural product. A significant finding is that the bromine atoms in ceratamine A contribute significantly to the antimitotic potency of the compound necessitating a bioisosteric approach to more potent antimitotic ceratamine-based agents.

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