Date of Award
Ph.D. in Pharmaceutical Sciences
Mark T. Hamann
Mitchell A. Avery
During the past three decades, the development of marine natural products as drug leads has become a promising avenue for research. As our efforts towards the discovery of anticancer and antibiotic drug leads from marine organisms, modifications of anticancer drug candidate kahalalide F, isolations of new peptides from the mollusk, Elysia rufescens and anticancer drug leads from the NCI repository, as well as chemical regulation of antibiotic production from marine Pseudomonas aeruginosa were investigated. Kahalalide F (KF) is a potent anticancer lead isolated from the herbivorous marine mollusk E. rufescens and its algal diet Bryopsis pennata. Our semisynthesis approach was aimed to improve the efficacy or prolong the half-life resulted in 15 KF analogues. These analogues included eight elongation products with nonpolar amino acid residues, four analogues with modified amino group at the Orn residue, one dehydration product of KF, and two new cyclization products of kahalalide G. All the analogues are being evaluated by Wayne State University for solid tumor cytotoxicity. In the course of the isolation of KF as starting material for its analogues, nine new and 10 known peptides were isolated from E. rufescens. However, only five structures were determined and the remaining four structures could not be assigned due to limited sample amounts (less than 1 mg). Future work will focus on the structure assignment using FTMS amino acid sequence analysis or 700 MHz NMR. During the screening of anticancer drug leads from the NCI repository, 27 extracts from marine organisms were tested, and 12 known compounds including tetracyclic aromatic alkaloids, diterpenoids and pyrroloaminopropylimidazole alkaloids were purified. Bioassay-guided isolation from marine P. aeruginosa collected in the Gulf of Mexico afforded 15 known antibiotics including two phenazines, six 2-alkyl-4-quinolones, and seven rhamnolipids. 2-Nonyl-4(1H)-quinolone and 2-(1-nonenyl)-4(1H)-quinolone displayed potent antimalarial activity, which was first reported here. Based on the metabolic profile of antibiotics from P. aeruginosa, chemical regulation and its impact on the yield of these metabolites were investigated. Treatment of P. aeruginosa with sceptrin and co-culturing with another Pseudomonas sp. increased antibiotic production significantly. This could be attributed to the activation of antibiotic biosynthetic gene expression under stress conditions.
Wang, Bin, "Anticancer and antibiotic leads from marine organis" (2012). Electronic Theses and Dissertations. 1499.