Exploring bio-active natural products as potential therapeutics leads

This thesis describes screening, mechanistic studies, design and synthesis of natural product analogs. Chapter 2 describes screening of a natural products library for their antibacterial activity against a panel of Gram (-) ve and Gram (+) ve bacteria including penicillin and methicillin resistant Staphylococcus aureus (MRSA). Through screening the compound library, several hits were identified, including psammaplysin F, which was a unique prokaryotic cell division inhibitor.Chapter 3 discusses screening a series of anthraquinone-based natural products and structure-activity relationship (SAR) studies against human colon cancer cell line HCT116. In this screening project a novel molecule, (1S, 3S)-austrocortirubin was identified that induces DNA damage. Although similar in structure to doxorubicin, (1S, 3S)-austrocortirubin exhibited a unique mechanism of action that was distinct from doxorubicin. Mechanistic studies showed that the treated cells stopped the G2/M phase check-point and mitosis, and caused significant DNA damage.In addition to screening, a series of linked azoles has been synthesized and their biological activity was evaluated. Chapter 4 explains the details of design and synthesis of the azoles and the SAR studies accomplished. In this project a specific trithiazole was observed to induce DNA damage and produced G2/M cell cycle arrest and activation of the G2/M DNA damage checkpoint. Given the success of these trithiazole compounds, we felt it would be useful to synthesize the natural product Marthiapeptide A, which incorporates linked trithiazole active structure. Thus, the second part of chapter 4 describes the routes towards the synthesis of the natural product Marthiapeptide A (Marth A), which was isolated by Zhao et al. in 2012 from the marine bacteria Marinactinospora thermotolerance. This molecule exhibited potent anticancer activity against a panel of human cancer cell lines when isolated as a natural product. It has a unique structure with three linked thiazoles coupled to a thiazoline system and turned into a macrocycle with the inclusion of a dipeptide. Two routes towards the synthesis of Marthiapeptide A have been outlined, where one route failed, and the second appears likely to succeed