Graduation Year
2006
Document Type
Dissertation
Degree
Ph.D.
Degree Granting Department
Chemistry
Major Professor
Mark McLaughlin, Ph.D.
Keywords
Constrained cyclic urea, NPA's, Substituted OPGDA's, Oxaziridine, Apoptosis
Abstract
HIV-1 protease binds to its peptide/protein substrates in extended conformations. Therefore protease inhibitors that are constrained to form extended conformations are likely to produce very active protease inhibitors. This is because they are pre-organized to form favorable interactions with the enzyme environment immediately surrounding the active site. With this hypothesis in mind, we designed a family of structurally related molecules, which contain dipeptide analogs constrained to adopt the extended conformation. Core structural intermediates that are required for the total synthesis of the novel class of HIV-1 protease inhibitors are outlined in Chapter One. Chapter Two discusses the enantioselective synthesis of 2-alkyl-3-nitropropionates (NPA's) that is the part A of the cyclic urea molecule 8, and can also be used as the building block for the synthesis of unnatural beta-amino acids.
In conclusion on this project, we were able to successfully achieve the novel enantioselective route for the synthesis of NPA's and also obtain the absolute stereochemistry of one of the NPA's by solving the crystal structure. Various routes were explored for the synthesis of the substituted orthogonally protected geminal diamino acids (OPGDA's) and these were discussed in Chapter Three. Chapter Three also discusses the synthesis of a versatile N-Boc transfer reagent and the applications of it in the synthesis of alpha-helix mimics. The outcomes of this project were the efficient synthesis of oxaziridine (104) and the methods that show how we cannot make the "substituted OPGDA's" which can serve as the guidance for future research on them. The proteasome is cellular machinery that is responsible for the breakdown of the complex proteins that are not required by a living cell. The inhibition of its activity in cancerous cells can promote apoptosis.
Chapter Four discusses the synthesis of a new class of 20S proteasome inhibitors, their biological testing and lead optimization by molecular modeling, library synthesis and biological evaluation. In short this project achieves our goal for the synthesis of a novel class of 20S proteasome inhibitors that have a potential to act as drug molecules in the future.
Scholar Commons Citation
Avancha, Kiran Kumar Venkata Raja, "Design and synthesis of core structural intermediates for novel HIV-1 protease inhibitors & synthesis, biological activity and molecular modeling of novel 20S proteasome inhibitors" (2006). USF Tampa Graduate Theses and Dissertations.
https://digitalcommons.usf.edu/etd/2447
