Synthetic efforts towards the natural products brocazine F and G



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The brocazines are a family of natural products bearing a disulfide diketopiperazine core that was isolated by Meng et al in 2014 and 2016 from an endophytic fungus derived from the marine mangrove plant Avicennia marina named Penicillium brocae MA-231. Seven different brocazines (A-G) and three different spirobrocazines were isolated, and of those brocazine F showed the strongest activity against prostate cancer cell line DU145 (IC₅₀ of 1.7 μM) and lung cancer cell line NCI-H460 (IC₅₀ of 0.89 μM). Brocazine G showed strong activity against ovarian carcinoma cell line A2780 (IC₅₀ of 0.664 μM), Ovarian endometrioid adenocarcinoma A2780 CisR cells (IC50 of 0.661 μM) as well as possessing strong and selective activity against human pathogen Staphylococcus aureus (MIC of 0.25 μg/mL). Given the potent cytotoxicity of brocazine F and G and their intriguing polycyclic core structure, our laboratory devised a total synthesis route to access this family. By focusing on these compounds, we envision the construction of a screening library yielding a new series of small molecules; which can be accessed through the intermediates of the total synthesis route employed for the construction of brocazine F and G. Each intermediate will serve as the starting material for a unique set of small molecules, structurally different from the original natural product, but potentially having unique and potent biological activity. Therefore, the goal of this dissertation is to establish a reliable and reproducible route to access the brocazine family of diketopiperazine (DKP) natural products, from which the intermediates can be amendable for chemical derivatization for complex screening library construction.



organic chemistry, total synthesis

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Doctor of Philosophy


Department of Chemistry

Major Professor

Ryan Rafferty