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

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.

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Title: ScienceOpen Posters

Publisher: ScienceOpen

Publication date (Electronic preprint): 1 May 2024

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[1 ] Empower College and Career Center;

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[* ]Email: director@ 123456syonlabs.org .

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Syon Schlecht https://orcid.org/0000-0001-6177-6150

Article

DOI: 10.14293/P2199-8442.1.SOP-.PWB2BX.v1

SO-VID: 5c448350-3132-4308-9579-6ac88ae8fd93

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This work has been published open access under Creative Commons Attribution License CC BY 4.0 , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Conditions, terms of use and publishing policy can be found at www.scienceopen.com .

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Date received : 1 May 2024

References

Duff Michael R., Gabel Scott A., Pedersen Lars C., DeRose Eugene F., Krahn Juno M., Howell Elizabeth E., London Robert E.. The Structural Basis for Nonsteroidal Anti-Inflammatory Drug Inhibition of Human Dihydrofolate Reductase. Journal of Medicinal Chemistry. Vol. 63(15):8314–8324. 2020. American Chemical Society (ACS). [Cross Ref]
Selhub Jacob, Dhar G. Jeelani, Rosenberg Irwin H.. Inhibition of Folate Enzymes by Sulfasalazine. Journal of Clinical Investigation. Vol. 61(1):221–224. 1978. American Society for Clinical Investigation. [Cross Ref]
Bowden K, Hall A D, Birdsall B, Feeney J, Roberts G C K. Interactions between inhibitors of dihydrofolate reductase. Biochemical Journal. Vol. 258(2):335–342. 1989. Portland Press Ltd. [Cross Ref]

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[1] Duff Michael R., Gabel Scott A., Pedersen Lars C., DeRose Eugene F., Krahn Juno M., Howell Elizabeth E., London Robert E.. The Structural Basis for Nonsteroidal Anti-Inflammatory Drug Inhibition of Human Dihydrofolate Reductase. Journal of Medicinal Chemistry. Vol. 63(15):8314–8324. 2020. American Chemical Society (ACS). [Cross Ref]

[2] Selhub Jacob, Dhar G. Jeelani, Rosenberg Irwin H.. Inhibition of Folate Enzymes by Sulfasalazine. Journal of Clinical Investigation. Vol. 61(1):221–224. 1978. American Society for Clinical Investigation. [Cross Ref]

[3] Bowden K, Hall A D, Birdsall B, Feeney J, Roberts G C K. Interactions between inhibitors of dihydrofolate reductase. Biochemical Journal. Vol. 258(2):335–342. 1989. Portland Press Ltd. [Cross Ref]

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