Structured unnatural molecules: Inducing molecular folding, enabling matured mammalian cell adhesion and inhibiting bacterial biofilm formation.

摘要

In nature, well-folded biomolecules including DNA, RNA, proteins and viruses perform a critical role in the functioning of life processes. To harness this power of nature, it is of significant interest to develop synthetic molecules that can replicate the function of these biopolymers such that these small man-made molecules can be engineered to perform nature's work in a test tube. The primary aim of this doctoral thesis is to design and synthesize by chemical methods, small unnatural molecules that offer a new perspective into the functioning of key biological events such as molecular folding, control of cell adhesion and bacterial biofilm formation.;The first chapter describes the application of chiral C3-symmetric bowl-shaped structures to induce molecular folding. The innate dissymmetry in these chiral bowls is utilized to induce weak intramolecular non-covalent forces that direct the local and global conformational ensemble of the molecules.;The second chapter describes the design and development of molecules with polyhedral point group symmetries T, O and I. These symmetry point groups are common in nature but are surprisingly inaccessible in most cases due to a lack of synthetic design that satisfies the rigorous symmetry requirements necessary for the development of these molecules.;The third chapter discusses the development of new strategies that govern the control of mammalian cell adhesion. Here, we have synthesized squarate-based small molecules that mimic the integrin-binding (Arg-Gly-Asp) domain on the extracellular matrix proteins. Using thiol-gold based self-assembled monolayers chemistry, surface immobilization with squaramide enhances matured mammalian cell adhesion suggesting small integrin blocking molecules may actually signal the cells to generate greater cell adhesion proteins, thereby, leading to drug failure. This work has profound implications in future drug design of integrin antagonists.;The fourth chapter describes the control of biofilm growth of E. coli and its subsequent dispersion by use of squarylated homoserine lactones (SHLs) mimics of N-acylhomoserine lactone-based quorum sensing signals. The SHLs are non-toxic and possess excellent biofilm inhibitory prowess at micromolar concentrations. Our studies demonstrate SHLs significant ability to modulate quorum sensing and this new class of inhibitors can be fine tuned to target persistent and pathogenic bacteria.