| Notes: | Advisor: Sergey A. Kozmin.
Includes supplementary digital materials.
Thesis (Ph.D.)--The University of Chicago, Division of the Physical Sciences, Department of Chemistry, 2009.
Dissertation Abstracts International, Volume: 70-12, Section: B, page: 7571.
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| Summary: | This dissertation describes the synthesis of small-molecule libraries that enabled the discovery of new bioactive chemotypes.
The first chapter describes the design and synthesis of a 955-member pyrrolidinone-based small-molecule library. Central to the synthetic strategy was the Michael addition of enamines with maleic anhydride and subsequent spontaneous cyclization to afford this heterocyclic core, which was further elaborated through amide formation. High-throughput screen of the library led to the discovery of a new inhibitor of acetylcoenzyme A carboxylase.
The second chapter describes the synthesis of a 936-member benzodiazepine-based small-molecule library. High-throughput cell-based screen of the library resulted in the discovery of triazatricyclamide A, a submicromolar cytotoxic chemotype. Our results indicate that triazatricyclamide A induces programmed cell death in HL-60 cells through a unique mechanism, which is characterized by an early onset of oxidative stress independent of mitochondrial function.
The third chapter describes our work on the synthesis of a small-molecule library that consists of multiple skeletal variations. Our strategy is based on enyne chemistry and [4+2] cycloadditions, followed by alkene functionalization through Os-catalyzed dihydroxylation and subsequent carbamate formation. The approach will be applied to the assembly of a scaffold-unbiased small-molecule library.
Experimental procedures are included in the fourth chapter. NMR spectra are available in Appendix A. Plate maps, TLC and NMR analysis of the pyrrolidinone-based library (Appendix B) and the benzodiazepine-based library (Appendix C) are included in separate, supplementary files.
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