Xin Zhang

Defense Date


Graduation Date



Immediate Access

Submission Type


Degree Name



Medicinal Chemistry


School of Pharmacy

Committee Chair

Aleem Gangjee

Committee Member

Marc W. Harrold

Committee Member

Patrick T. Flaherty

Committee Member

David J. Lapinsky


Thymidylate synthase (TS), dydrofolate reductase (DHFR), glycinamide ribonucleotide formyltransferase (GARFTase)


An introduction, background and research progress in the areas of antifolates, receptor tyrosine kinase (RTK) inhbitors and anti mitotic agents has been 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. Classical antifolates, in most cases, are substrates for folypoly - γ - glutamate synthase (FPGS) and rely on folate transporter systems to enter cells. As a part of this study, twenty - eight compounds were designed on the basis of existing clinically active compounds and crystal structures, synthesized and evaluated as single and/or muliple targeted classical and nonclassical antifolates to decrease toxicity and improve the activity and selectivity of existing therapeutic agents. In additio n, these structures provides an extension to the structure activity relationship in the antifolate area.

RTK inhibitors and antimitotic agents are important antitumor agents and are extensively used in the clinic for the treament of various types of cancer s. Pgp overexpression is one of the common reasons for drug resistance to existing antitumor agents and consequently the reason for some chemotherapeutic failures. A furo[2,3- d ]pyrimidine compound was discovered to have dual RTK inhibitory activity along with antimitotic activity that circumvent pgp over expression. Antimitotic activity via the binding at the colchicine site is one of the mechanisms of action. Molecular modelling and biological evaluation suggest the importance of conformational restriction for activity. Fifty - seven furo[2,3- d ]pyrimidines and six thieno[2,3- d ]pyrimidines were designed on iv the basis of crustal structures and synthesized as potential RTK inhibitors with antimitotic antitumor activity. Four pyrrolo[2,3- d ]pyrimidines were design ed and synthesized as antimitotic anticancer agents that also reverse pgp action.