Defense Date

3-5-2014

Availability

Worldwide Access

Submission Type

dissertation

Degree Name

PhD

Department

Medicinal Chemistry

School

Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences

Committee Chair

Aleem Gangjee

Committee Member

Marc Harrold

Committee Member

David Lapinsky

Committee Member

Patrick Flaherty

Keywords

Antiangiogenic agents, antimitotic agents, combination chemotherapy, endothelial growth factor receptor-2, single agents, tubulin

Abstract

This dissertation describes the design, synthesis and biological evaluation of pyrimidine fused heterocycles as single agents with combination chemotherapy potential. Major limitations of cancer chemotherapy include dose limiting toxicities of clinically used agents and the development of multidrug resistance by the tumor. Agents that interfere with microtubules are important antitumor agents. Tumor angiogenic mechanisms that are vital for tumor growth and metastasis are targeted by antiangiogenic agents. Antiangiogenic agents are usually not tumoricidal but are mainly cytostatic. Combination chemotherapy with antiangiogenic and cytotoxic agents have shown significant promise and several studies with such combinations are in progress in the clinic. Single agents with both antiangiogenic activities as well as cytotoxicity would afford single agents that circumvent pharmacokinetic problems of multiple agents, avoid drug–drug interactions, could be used at lower doses to alleviate toxicity, be devoid of overlapping toxicities, and delay or prevent tumor cell resistance. The work in this dissertation is centered on the design and synthesis of single entities that have both antiangiogenic effects and cytotoxic effects.

These efforts led to the identification of structural features that are necessary for inhibition of tubulin polymerization. Structural modifications also led to the identification of novel antiangiogenic agents which inhibit one or more of the receptor tyrosine kinases (RTKs)– vascular endothelial growth factor receptor–2 (VEGFR2), platelet derived growth factor receptor–β (PDGFRβ) and epidermal growth factor receptor (EGFR). The complexity of the angiogenic pathways in tumors implies that disrupting a single mechanism of angiogenesis may not result in significant clinical success. Multiple RTKs are co–activated in tumors and redundant inputs drive and maintain downstream signaling, thereby limiting the efficacy of therapies targeting single RTKs.

This work reviews the role of RTKs in angiogenesis, microtubules as antitumor targets, the vascular normalization theory and multitargeted agents. This work also reviews the synthesis of substituted pyrrolo[3,2–d]pyrimidines, furo[3,2–d]pyrimidines, pyrimido[5,4–b]indoles and b]. A discussion of methods employed in the synthesis of pyrimidine fused heterocycles as single agents with combination chemotherapy potential is provided.

Format

PDF

Language

English

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