UC Davis

Bioisosteric replacement in drug design allows medicinal chemists to alter deleterious effects and/or improve the physicochemical properties of small molecule drugs while maintaining their overall efficacy. Lipophilic pharmacophores are being recognized for having similar importance and influence on ADMET properties as has been seen with hydrophilic groups; however, there are far fewer lipophilic bioisosteres compared to their hydrophilic counterparts. The lipophilic pharmacophore space is ripe for expansion. This dissertation explores the utility and implementation of silyl-lipid tails into bioactive molecules for proof-of-concept studies. The introduction gives a brief overview of bioisosteric replacements and specific case studies emphasizing the importance of lipophilic pharmacophores on physicochemical properties. Properties and reactivity of silicon are discussed in comparison to carbon. The construction of organosilicon frameworks is discussed using hydrosilylation and aryl silylation reactions. Chapter one presents the relevant chemical biology of bacterial cell communication known as quorum sensing (QS) and the development of new silyl-lipid signaling molecules. Three target classes of silyl-lipid N-acylated homoserine lactones (AHLs) were designed and synthesized based on native QS signals and previously identified lead compounds. Amidation, hydrosilylation, and aryl silylation conditions were screened for reactivity and underwent optimization to access a total of 17 novel silyl-lipid AHLs. The silyl-lipid AHLs were evaluated for biological activity by Emma Santa and Irene Stoutland in the Blackwell Lab at the University of Wisconsin, Madison. Molecular docking studies were also conducted to inform upon synthetic targets. A subset of silyl-lipid AHLs also underwent biophysical characterization via liposome formation and dynamic light scattering measurements (performed by Cole Dickson under my mentorship at University of California, Davis). Chapter two discusses the structure-activity relationships of THC and CBD derivatives and the pharmacology of targeting cannabinoid receptors: CB1R and CB2R. Preliminary biological assay data from our lab, in conjunction with the breadth of data on CB1R vs. CB2R selectivity, informed the selection of synthetic targets to be explored. In the pursuit of CB2R selectivity, several novel silyl-lipid CBD compounds were designed and synthetic conditions were investigated. A route to Si-HU-308 derivatives was investigated and appropriate conditions were identified for a key oxidation step. Efforts to simplify the route to Si-CBD analogues by shortening the terpenoid synthesis were thoroughly explored. The Appendix contains all relevant NMR data.