Author

Xilin Zhou

Defense Date

9-6-2012

Graduation Date

2012

Availability

Immediate Access

Submission Type

thesis

Degree Name

MS

Department

Medicinal Chemistry

School

School of Pharmacy

Committee Chair

Aleem Gangjee

Committee Member

Patrick Flaherty

Committee Member

David Lapinsky

Keywords

Antifolate, Drug design, SAR

Abstract

An introduction, background and research progress in the areas of antifolates and antimitotic agents has been reviewed and discussed. Thymidylate synthase (TS), dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyltransferase (GARFTase) are important folate dependent enzymes that are targets for cancer chemotherapy and the treatment of infectious diseases. As a part of this study, thirty-five novel compounds were designed and synthesized on the basis of existing clinically active compounds and their crystal structures. These compounds were synthesized and evaluated as single and/or muliple targeted classical and nonclassical antifolates to decrease toxicity and improve the antitumor activity and selectivity of existing therapeutic agents. In addition, bicyclic substituted thieno[2, 3- italic d /italic ]- and theino[3, 2- italic d /italic ]pyrimidines were synthesized as antimitotic agents. These compounds allowed potent inhibition of tumor cells in culture and extended the structure-activity relationship in the antimitotic area.

Format

PDF

Language

English

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