Bioorganic Chemistry of Prodigiosenes: Anion Transport, Basicity, Conformation and G-Quadruplex DNA Binding
Davis, Jeffery T
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Naturally occurring prodigiosenes are produced by microorganisms such as Streptomyces and Serratia marcescens. Prodigiosenes are fascinating for their wide range of biological activities in the form of anti-cancer, immunosuppressive, and antimicrobial agents. Some of the analogs, such as prodigiosin, are currently undergoing preclinical and clinical trials. Despite such widespread interest, the origin of prodigiosin's biological activity has not been established unambiguously. Based on biological studies, it is known that prodigiosin plays a physiologically relevant role and has several cellular targets. The work described in this thesis explores some of the chemistry that may help explain prodigiosenes' biological activity. A new series of analogs of prodigiosin bearing an additional methyl and a carbonyl group at the C-ring were evaluated as transmembrane anion transporters. The effect of C-ring modifications in these new prodigiosenes on their basicity, transmembrane anion transport ability and their in vitro anticancer activity was assessed. The ability of prodigiosenes to facilitate co-transport of H⁺Cl⁻ leading to alteration of intracellular pH, and catalyze anion exchange across lipid bilayers has been proposed to be one of the cause of its anti-cancer activity. It has been suggested that the prodigiosenes bind anions in their protonated state at physiological pH. Prodigiosene analogs with modified B-ring demonstrated that the electronic nature of the substituent on the B-ring influences the basicity of these analogs, and consequently, their anion transport efficiency is also affected. A study of the conformations of prodigiosin and its analogs was performed to learn about how the ligands orient in different solvents. This information could potentially link the preferred conformational states of these compounds and their observed biological activities. Lastly, we confirmed that prodigiosin binds at the 3ˈ end of a G-quadruplex DNA. The results from this chapter are significant as they widen the scope of developing prodigiosenes as G-quadruplex binding ligands or telomerase inhibiting agents. Further, they lead the way to revealing another possible mechanism to explain the anti-cancer activity of prodigiosenes.