ADVANCES IN SYNTHESIS AND APPLICATIONS OF ARTIFICIAL CELL SURFACE RECEPTORS AND METHODOLOGY FOR PREPARATION OF
NOVEL ANTIVIRAL AGENTS

Sun, Qi

ADVANCES IN SYNTHESIS AND APPLICATIONS OF ARTIFICIAL CELL SURFACE RECEPTORS AND METHODOLOGY FOR PREPARATION OF NOVEL ANTIVIRAL AGENTS

Open Access

Author:

Sun, Qi

Graduate Program:

Integrative Biosciences

Degree:

Doctor of Philosophy

Document Type:

Dissertation

Date of Defense:

September 29, 2008

Committee Members:

Joseph M Bollinger Jr., Dissertation Advisor
Joseph M Bollinger Jr., Committee Chair
Professor Blake R Peterson, Committee Chair
Avery August, Committee Member
Gong Chen, Committee Member

Keywords:

nucleoside triphosphate
cholesterylamine
synthetic receptors
endosome disruption

Abstract:

In the past decade, our group has developed a novel technology that can be used to dramatically enhance uptake of cell impermeable macromolecules by mammalian cells. By mimicking small natural cell surface receptors, synthetic receptors, composed of N-alkyl-3â-cholesterylamine membrane anchors linked to protein-binding motifs, can be installed on cell surfaces. Mechanistic studies have revealed that similar to certain natural cell surface receptors, the synthetic receptors internalize cargo molecules through a clathrin-mediated endocytic pathway. However, the lack of an efficient method for the synthesis of 3â- cholesterylamine has limited the development of this technology. Additionally, trapping of molecules delivered by synthetic receptors in confined intracellular compartments, endosomes, restricts potential applications of this delivery system. To address these issues, we developed novel and practical methodologies for the large-scale preparation of 3â-cholesterylamine and related building blocks; we also designed and synthesized novel 3â-cholesterylamine-capped PC4 lytic peptides, which enable 3â-cholesterylamine-conjugated cargo bearing a disulfide linkage to selectively escape from early/recycling endosomes of living mammalian cells. Furthermore, study of the interactions of C-reactive protein with phosphocholine-containing synthetic receptors led us to the discovery of a novel method to promote apoptosis in Jurkat lymphocytes. The other area of my research focused on the development of novel methodologies for the preparation of antiviral agents and their phosphoylated metabolites. A novel one-pot approach for the synthesis of nucleoside 5’- triphosphates from nucleoside 5’-H-phosphonate monoesters was explored. We demonstrated that fully deprotected 5’-H-phosphonates of antiviral nucleosides can be converted via pyridinium phosphoramidate intermediates to the corresponding 5’-triphosphate products, which can be readily purified using a two-step purification protocol. We also constructed a small 39-member library based on a vinylbenzimidazolium Akt inhibitor through the discovery of a novel and efficient Zr(IV)-catalyzed cyclization of substituted 1,2-arylenediamines and á,â-unsaturated aldehydes.Biological screening of the new compound library identifed four compounds with greater antiviral activity than the lead compound.