Defense Date
11-19-2024
Graduation Date
Winter 12-20-2024
Availability
One-year Embargo
Submission Type
thesis
Degree Name
MS
Department
Medicinal Chemistry
School
School of Pharmacy
Committee Chair
Aleem Gangjee
Committee Member
Patrick T. Flaherty
Committee Member
Marc Harrold
Keywords
Antifolates, Pemetrexed, Methotrexate, Dose-limiting toxicity, chemotherapeutics agents
Abstract
In cancer chemotherapy, the currently marketed antifolates have two major disadvantages: dose-limiting toxicities to normal tissues and susceptibility to drug resistance. These are due to their major transport by the ubiquitously expressed transporter and mutagenesis in enzymes present in cancer cells. This thesis describes an introduction, background, and research progress in antimetabolites-antifolates designed to multi-target (a) one-carbon metabolism and de novo nucleotide synthesis pathway and (b) target overexpressed transporter in cancer cells for selective tumor-targeting.
Cancer cells transport folate through three transporters: ubiquitously expressed reduced folate carrier (RFC), limitedly expressed proton-coupled folate transporter (PCFT), and folate receptors (FRs). The research strategies that have developed drugs that target PCFT and/or FRs transporter, which could only minimize the dose-limiting toxicity issue through specificity for cancer cells. To address the mutagenesis/ drug resistance issue, one must target multiple enzymes such that the cancer cells can not simultaneously mutate multiple targets. Moreover, in cancer cells, one-carbon metabolism enzymes supported by folate metabolism are known to be upregulated and serve to activate multiple biosynthetic processes, including de novo purine and thymidine synthesis and homocysteine remethylation, required for their proliferation and survival. Thus, the next valid step is to design and synthesize compounds that can address mutagenesis/drug resistance and toxicity issues by targeting multiple one-carbon metabolism enzymes along with transport specificity in cancer cells.
Pemetrexed (PMX), initially named as a multitargeted antifol (MTA) and now with the trade name Alimta, was approved for several cancers, including non-small-cell lung cancer and mesothelioma, and has three disadvantages: (1) Its major transport is by the ubiquitously expressed RFC; (2) It is dependent on its polyglutamylation for potency, and (3) It has developed resistance due to mutagenesis in folypolygultamate synthase (FPGS), thymidylate synthase (TYMS) and dihydrofolate reductase (DHFR). The work in this thesis involves the design and the development of a part of a pipeline of pyrrolo-pyrimidine antifolates that are superior to PMX as they circumvent the disadvantages of PMX.
Language
English
Recommended Citation
Magdum, T. (2024). DESIGN, SYNTHESIS, AND CHARACTERIZATION OF MULTI-TARGETING PYRROLOPYRIMIDINE ANTIFOLATES AS POTENTIAL SINGLE AGENT CHEMOTHERAPEUTIC ENTITIES (Master's thesis, Duquesne University). Retrieved from https://dsc.duq.edu/etd/2411