I. Stereochemical Control of Chiral Assembly and Liquid Crystal Phase Formation of Nonamphiphilic Molecules in Water II. Control Bacterial Quorum Sensing and Quorum Sensing-mediated Activities Using Small Unnatural Molecules

The primary goal of this research is to utilize organic synthesis as a tool to prepare small molecules that find potential application in different areas including colloidal and material science, biological chemistry, and medicinal chemistry. Chapter 1 describes the interpretation of the conformation of nonamphiphilic mesogen disodium cromoglycate (5´DSCG) when it exists as part of an assembly in water. The study of thermodynamic incompatibility and miscibility suggest that a previously proposed model for the assembly of 5´DSCG may be applicable to nonamphiphilic organic dyes and other mesogens. Chapter 2 presents a study of stereochemical control on assembly and liquid crystal formation by nonamphiphilic molecules. Three stereoisomers of a disodium chromonyl carboxylate derivative, 5´DSCG-diviol, were designed and synthesized. The chiral stereoisomers formed chiral nematic liquid crystals while the achiral counterpart did not form any kind of liquid crystals. The hydrated assemblies of chiral 5´DSCG-diviol were able to interact with each other across a 6 nm separation in aqueous environment and the chirality information was transmitted through achiral medium. Chapter 3 describes the synthesis and biological studies of a class of bicyclic brominated furanones. These molecules interacted with quorum sensing in an opportunistic pathogen P. aeruginosa. Some representative compounds in this class inhibited quorum sensing-controlled activities such as biofilm formation and virulence factor production, which were key factors in the pathogenicity of the bacteria. These compounds exhibited significant reduction in the toxicity of human neuroblastoma SK-N-SH and did not inhibit bacterial growth. Furthermore, one compound, 6-BBF, significantly improved P. aeruginosa clearance in the lungs of mice in an immunocompromised pneumonia mouse model in vivo. Chapter 4 reports the synthesis of a library of squarylated homoserine lactones (SHLs) as analogues to the natural autoinducers N-acyl homoserine lactones (AHL) in Gram-negative bacteria. These SHLs were shown to have no or minimal impact of the growth of P. aeruginosa and V. fischeri, but maintain the abilities to modulate quorum sensing and inhibit biofilm formation. Primary studies of structural activity relationship revealed that the alkyl chain length was critical to activities of SHLs. These SHLs are promising candidates as modulators of other AHL-mediated QS systems