A comprehensive reinvestigation into the bioactive secondary metabolites of an Indo-Pacific marine sponge: Cacospongia mycofijiensis

The contents of this dissertation describes the chemical examination of multiple collections of an Indo-Pacific marine sponge, Cacospongia mycofijiensis, as well as a Red Sea sponge, Negombata magnifica in an effort to enable future studies of the biosynthetic pathways produced from these sources, discover novel chemistry, probe for interesting biological activities and ultimately develop therapeutic leads through preclinical investigation. This was accomplished through an analysis of the biogeographical variations of the secondary metabolites found within these species using LCMS-ELSD, followed by purification of new and known metabolites to identify biological activities, establish the optimal pharmacophore through structure activity relationships (SAR) and lastly identify lead compounds to undergo in vivo evaluation. Twenty-three sponges varying in collection year and region were profiled in this work resulting in the disclosure of two unique structural classes and the discovery of over a dozen new compounds which include latrunculone B, CTP-431, the aignopsanes and the fijianolides D-I.;The first chapter begins with an introduction to terrestrial and marine natural products chemistry, their inception and some of the major contributions that have been made from each field. This chapter ends with concluding remarks on the current status and future of marine natural products chemistry. The following chapters describe the research carried out in this dissertation.;The contents of chapter two explores the chemistry of the microfilament destabilizing latrunculin A and B family to gain further insight into their cytotoxicities as well as the nature of the bioactive pharmacophore. This chapter focuses on the chemistry of Fijian (C. mycofijiensis) and Israeli (N. magnifica) sponge collections and results in the discovery of new analogs, a possible alternate mode of action for the latrunculins, as well as the disclosure of an unprecedented natural product thiopyrone, CTP-431 which is biogenetically related to latrunculin A. The microfilament activity and cytoxicity of these compounds against murine and human solid tumor cell lines using a cytoskeletal and disk diffusion soft agar colony formation assay are described in this chapter along with the structural characterization of a new major metabolite latrunculone B and CTP-431.;The third chapter involves the recollection and reinvestigation of Papua New Guinea specimens of C. mycofijiensis, which were devoid of published chemistry. This project initially focused on probing for new analogs of known chemotypes to further explore their biologically active properties. Its emphasis rapidly changed direction upon the discovery of a series of novel secondary metabolites. Accelerated Solvent Extraction (ASE) and LCMS-ELSD analysis of 18 individual collections of C. mycofijiensis resulted in the isolation and characterization of a new class of sesquiterpenes, the aignopsanes, along with the first report of the fijianolides and mycothiazole from Papua New Guinea collections.;The final chapter includes chemical investigations into the microtubule stabilizing agents of the fijianolide (syn. laulimalide) class in hopes of establishing a more complete understanding of their structure activity relationships. Vanuatu collections of C. mycofijiensis were a source of six new fijianolides (D-I) along with the fijianolides A and B which were isolated, characterized and evaluated against two human solid tumor cell lines and identified fijianolide B as the lead member of this class. An in vivo evaluation of fijianolide B using human tumor-bearing severe combined immuno-deficient mice demonstrated significant inhibition of growth in HCT-116 tumors over 28 days.*;*Please refer to dissertation for diagrams.