Characterization of new marine secondary metabolites for the treatment of cancer and neglected tropical diseases

Small molecules from natural sources are vital to drug discovery by providing molecular diversity and novel chemical scaffolds for further pharmacological development. The emergence of multiple drug resistant pathogens and problems associated with natural product dereplication emphasize the continuing need for the discovery of new and relevant bioactive molecules for the treatment of human disease. This thesis describes the biological activity guided chemical investigation of several marine taxa with emphasis on the isolation and structure elucidation of new secondary metabolites with therapeutic efficacy against cancer and infectious disease. Chapter I introduces the context, rationale and background which form the foundation of the thesis research. Chapter II describes the bioactivity guided discovery of a new cancer compound from a Panamanian marine cyanobacterium Symploca sp. The linear tetrapeptide contains unusual and modified amino residues and exhibits sub-micromolar cancer toxicity with a classic antimitotic mechanism of action. Chapter III describes the discovery of DMMC a new cyclic depsipeptide isolated from a Fijian strain of Lyngbya majuscula. The antitumor effects displayed by this compound were very potent and selective for solid tumor cell lines. A linear analog of DMMC was generated during structure determination, this analog proved to maintain the exquisite and selective activity of the parent molecule. Chapter IV describes the discovery of the viridamides A and B from the cyanobacterium Oscillatoria nigro-viridis. Structure elucidation of these linear lipodepsipeptides revealed the presence of the novel 5-methoxydec-9-ynonic acid residue and subsequent biological evaluation indicated low micromolar efficacy against two species of disease causing protozoan pathogens. Chapter V describes the bioassay guided isolation and structure elucidation of kaviol A, a halogenated phenolic inhibitor of histone deacetylase (HDAC) from a Papua New Guinean strain of the green alga Boodlea sp. This unique C₆-C₄-C₆ structure contains multiple sites of halogenations and inhibits six isoforms of class II HDAC enzymes with very low micromolar IC₅₀ values. Chapter VI provides a conclusion of this thesis researc