Small molecule modulation of biological systems

Synthetic organic chemistry can be a useful tool for probing and ultimately manipulating biological mechanisms. Small molecule synthesis allows for the generation of specific structural analogs of important biological compounds. These analogues can be used to modify the reactivity, three-dimensional structure, binding ability, stability, polarity, or many other characteristics of the natural molecule. These modifications can lead to new substrate agonists or antagonists; or, can be used to understand the mechanistic implications between substrate and enzyme. This thesis discusses our efforts towards small molecule manipulation of two important biological processes.;The first part of this thesis deals with apoptosis, or programmed cell death. This highly regulated process utilizes a series of protein interactions which control an apoptotic signal. This work focuses on one particularly important interaction: the binding of Smac (secondary mitochondrial activator of caspases) with XIAP (X-linked inhibitor of apoptosis protein). Smac is responsible for dislodging caspases, cysteine-aspartate proteases, from XIAP. Free caspases than begin a cascade signal which ultimately leads in cell death. Overexpression of XIAP has been associated with certain types of cancer cells. The binding interaction between Smac and XIAP occurs through the four N-terminal residues of Smac on the surface of XIAP. This project focuses on the generation of a series of a series of small molecule Smac peptidomimetics which are designed to probe the important characteristics for optimum binding interaction. The binding affinity of these mimics is evaluated by a competitive fluorescence binding assay. Ultimately, a small molecule Smac mimic optimized for stability and binding affinity with XIAP could lead to a new cancer treatment.;The second half of this thesis focuses on bacterial quorum sensing, a process by which bacteria control their population density via gene expression. This process is controlled by a series of small molecules known as autoinducers (AI's). System two quorum sensing has been implicated in interspecies bacterial communication, mediated communication amongst varied species of bacteria by a universal signal, S-4,5-dihydroxy-2,3-pentanedione (DPD). DPD is synthesized by the degradation of S-ribosylhomocysteine (SRH) by the enzyme LuxS. Bacterial resistance to traditional anti-bacterial therapies has resulted in the need for new approaches to control bacterial pathogenicity. Chemical modulation of interspecies bacterial quorum sensing provides an alternative to traditional antibiotics. This focus of this work was to design a series of SRH analogues which will inhibit LuxS. These analogues were designed to allow for efficient binding to the LuxS enzyme, but abrogate the decomposition of SRH to DPD. As a result, system two quorum sensing would be shut down and bacterial growth controlled.