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UBC Theses and Dissertations

Synthesis of bioactive natural products Zheng, Zehua

Abstract

Crude extracts of the rare macrofungus Serpula sp. collected from a wooded area in Sri Lanka showed antimicrobial activity. The novel fungal metabolite serpulanine (2.1) was isolated from the crude extract in very small amounts along with a number of additional secondary metabolites. In order to obtain sufficient quantities of serpulanine (2.1) for biological evaluation, a synthetic route was developed to the natural product and a small library of analogs that have been evaluated in a panel of bioassays. Serpulanine (2.1) inhibits the histone deacetylase I/II with a clear dose response curve. Halitoxins (3.1) that are frequently isolated from marine sponges have a complex macrocyclic chemical structure made of different numbers of monomeric alkylpyridinium units. An unknown halitoxin-related natural product named alotau potently inhibited the dephosphorylation activity of calcineurin. With the goal to elucidate the structure of alotau, compounds of one, two and three pyridinium rings (3.10, 3.7 and 3.8) were synthesized. Though these compounds have NMR spectra similar to the natural alotau, according to bioassay results, none of them recapitulates the activity of the unknown natural product alotau. (+)-Makassaric acid 4.1 was isolated in the Andersen Lab from the marine sponge Acanthodendrilla sp. It showed promising activity in a zebrafish screen for new drugs to treat stroke patients. The convergent synthetic scheme shown below was undertaken to conduct structure activity relationship (SAR) studies. The key intermediate 4.17 has been obtained, and further synthetic efforts will be needed to produce 4.1.

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