Exploring Salicylate Derivatives of Naproxen as DHFR Inhibitors: A New Therapeutic Avenue in Cancer Treatment

Abstract

Dihydrofolate reductase (DHFR) is an enzyme that catalyzes the conversion of DHF to THF, which is crucial for nucleotide synthesis. It has been the target of many chemotherapy drugs, such as Methotrexate, where inhibition of DHFR slows cancer growth. Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to competitively inhibit DHFR, hindering folate metabolism and cell proliferation. NSAIDs containing salicylate groups, such as diflunisal, have been shown to have the strongest binding activity. We synthesized salicylate derivatives of naproxen to explore DHFR inhibition, and characterized them through enzymatic assays and kinetics. The measured activity of DHFR allowed us to assess their binding affinity and inhibitory potency. Salicylate derivatives of naproxen emerge as promising DHFR inhibitors, offering therapeutic potential in modulating inflammatory pathways. Further optimization may yield more effective dual-targeted analogs.