Advancing the Preclinical Development of Secondary Metabolites from Cacospongia mycofijiensis for the Treatment of Cancer

Abstract

The marine sponge Cacospongia mycofijiensis from the Indo-Pacific has proven to be a source of structurally diverse secondary metabolites that are biologically active against a variety of distinct targets. Current interest in the secondary metabolites of C. mycofijiensis largely stems from a) their potent and preferential cytotoxicity for cancer cell lines versus normal cells, making many of them promising leads as cancer therapeutics and b) the novel mechanisms of action responsible for their impressive cytotoxicity. However, limited compound availability has resulted in a paucity of studies aimed at advancing the preclinical development of these secondary metabolites from C. mycofijiensis for the treatment of two cancers in need of additional effective therapeutics. The three lead chemotypes derived from C. mycofijiensis this thesis include are the mycothiazole, fijianolide B, and zampanolide chemotypes. We began our studies with purification of each of the three lead compounds and confirmation of their chemical characteristics by NMR spectroscopy and mass spectrometry. Following this, we generated analogs to study the cytotoxic structure activity relationship (SAR) and improve stability of labile chemotypes. We evaluated these chemotypes in a range of preclinical studies for the treatment of cancer, such as in vitro screening for preferential cytotoxicity against cancer cell lines, mechanism of action studies, and determining the maximum tolerated dose in mice. Data gathered from these preclinical studies showed the notable potency both in vitro against cancer cell lines and when evaluated using in vivo models, as well as provided important data on the SAR of compounds within their respective class. This ultimately provides valuable insight into the use of these three lead chemotypes as potential future therapeutics for the treatment of pancreatic cancer or triple-negative breast cancer.