Advisor(s)

Graham B. Jones

Contributor(s)

M. V. Sitkovskiĭ, Philip W. LeQuesne, Zhaohui S. Zhou

Date of Award

2008

Date Accepted

7-2008

Degree Grantor

Northeastern University

Degree Level

Ph.D.

Degree Name

Doctor of Philosophy

Department or Academic Unit

College of Arts and Sciences. Department of Chemistry and Chemical Biology.

Keywords

Chemistry, Organic chemistry, Tumor targeted therapy

Subject Categories

Tumor antigens, Cancer - Chemotherapy, Cancer - Immunotherapy

Disciplines

Medical Immunology | Medicinal-Pharmaceutical Chemistry

Abstract

Recently, the subject of tumor targeted therapy has drawn more and more attention as a result of increasing knowledge of biology and physiology. A tumor specific agent with high therapeutic index, good bioavailability and easy preparation is highly preferred. To achieve this goal, rational design and development of synthetic lead compounds based on active natural products remain as the most successful strategy in cancer chemotherapy. It serves as both the objective and the philosophy of this thesis and is demonstrated in the following two areas of research. Bulges are unpaired nucleotides on one strand of the DNA double helix. They have been linked to many biomolecular processes including cancer. Agents with high specificity to bulges would be of considerable utility to the biological research community for the discovery of active anti-tumor entities. NCSi-gb is a natural metabolite of neocarzinostatin chromophore (NCS chrom), an anti-tumor antibiotic. It was found to bind specifically to bulged DNA at nanomolar concentration due to its unique wedge-shaped spirocyclic structure. Modeled on the molecule, mimics of NCSi-gb were rationally designed and a synthetic route was devised and executed to prepare them. These analogues showed nanomolar binding affinity and two-base bulge specificity. In a second area of my research, tumor targeting is investigated using in a prodrug approach based on the A2A receptor mediated tumor escape mechanism in T-cells. A prodrug of KW6002, an 8-substituted xanthine, was designed and synthesized. The proof-of-principle study validated the design for enzyme activated drug release. A major obstacle to accessibility of this class of compounds is the tedious two-step cyclization for the formation of xanthine's five-membered rings. Therefore, a novel one-pot methodology for the preparation of 8-substituted xanthines was developed. Using this methodology, the key intermediate for the preparation of the tumor targeting prodrug was more efficiently synthesized, along with a number of analogues.

Document Type

Dissertation

Rights Holder

Dong Ma


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