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Thymidine kinase as a molecular target for the development of novel anticancer and antibiotic agents

Byun, Youngjoo
http://rave.ohiolink.edu/etdc/view?acc_num=osu1149008350

Abstract Details

2006, Doctor of Philosophy, Ohio State University, Pharmacy.
Thymidine kinase (TK), a key enzyme of the salvage pathway for DNA biosynthesis, is an attractive molecular target for the treatment of brain tumors and anthrax infections because of its high activity in tumor cells and its occurrence in pathogenic Bacillus anthracis. In tumor-related research, boron neutron capture therapy (BNCT) was chosen as the therapeutic modality. Previous structure-activity relationship (SAR) studies of 3-carboranyl thymidine analogues (3CTAs) identified one promising boron-delivery agent for BNCT, designated N5-2OH. Two feasible synthetic routes for the preparation of 10B-enriched N5-2OH were developed, which was evaluated as a boron-delivery agent for BNCT in pilot neutron irradiation experiments. Stereochemical- and geometrical N5-2OH isomers were synthesized and their substrate specificities for human thymidine kinase 1 (hTK1) were evaluated to complete SAR studies of the N5-2OH series. A computational model for the binding of the N5-2OH series to the active site of hTK1 was also developed. In order to improve physicochemical properties of 3CTAs, zwitterionic nido 3CTAs were synthesized and evaluated as boron-delivery agents for BNCT. One of these agents showed similar in vitro and in vivo biological activities as N5-2OH combined with superior physicochemical properties. The zwitterionic nido m-carborane system was further investigated. This novel type of boron cluster exhibited unique chemical features by reacting with the carbonyl group of ketones or aldehydes to afford zwitterionic iminum-substituted carboranes. In anthrax-related research, a compound library composed of 30 known antiviral and anticancer drugs was screened in phosphoryl transfer assays with B. anthracis TK and in growth inhibition studies with B. anthracis Sterne. Novel potential inhibitors of B. anthracis TK and of B. anthracis thymidine monophosphate kinase for the treatment of anthrax infections were designed as mimicks of thymidine triphosphate, the endogenous feedback inhibitor of B. anthracis TK. Twenty inhibitors were synthesized and evaluated biologically. Some of the inhibitors exhibited low IC50 values in growth inhibition studies with B. anthracis Sterne. Overall, the concept of novel antibiotics targeting B. anthracis TK was validated and two inhibitors were selected as lead compounds for further structural optimization.
Werver Tjarks (Advisor)
Robert Curley, Jr. (Other)
Pui-Kai Li (Other)
Thymidine kinase; Boron neutron capture therapy; N5-2OH; 3CTAs; Bacillus anthracis

Recommended Citations

Citations

  • Byun, Y. (2006). Thymidine kinase as a molecular target for the development of novel anticancer and antibiotic agents [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1149008350

    APA Style (7th edition)

  • Byun, Youngjoo. Thymidine kinase as a molecular target for the development of novel anticancer and antibiotic agents. 2006. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1149008350.

    MLA Style (8th edition)

  • Byun, Youngjoo. "Thymidine kinase as a molecular target for the development of novel anticancer and antibiotic agents." Doctoral dissertation, Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=osu1149008350

    Chicago Manual of Style (17th edition)

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© 2006, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.