DHFR Inhibitors: Reading the Past for Discovering Novel Anticancer Agents.

Maria Raimondi,Simona Collina,Giampaolo Barone,Mery La Franca,Ornella Randazzo,Elisa Vignoni,Daniela Rossi

doi:10.3390/molecules24061140

Maria Raimondi, Simona Collina + Show 5 more

Open Access

https://doi.org/10.3390/molecules24061140

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Abstract

Dihydrofolate reductase inhibitors are an important class of drugs, as evidenced by their use as antibacterial, antimalarial, antifungal, and anticancer agents. Progress in understanding the biochemical basis of mechanisms responsible for enzyme selectivity and antiproliferative effects has renewed the interest in antifolates for cancer chemotherapy and prompted the medicinal chemistry community to develop novel and selective human DHFR inhibitors, thus leading to a new generation of DHFR inhibitors. This work summarizes the mechanism of action, chemical, and anticancer profile of the DHFR inhibitors discovered in the last six years. New strategies in DHFR drug discovery are also provided, in order to thoroughly delineate the current landscape for medicinal chemists interested in furthering this study in the anticancer field.

Highlights

Since the middle of the last century, the potential of the dihydrofolate reductase (DHFR) enzyme as a therapeutic target for treating infections has been evidenced [1,2]
DHFR catalyzes the reduction of dihydrofolate to tetrahydrofolate using nicotinamide adenine dinucleotide phosphate (NADPH), and it is involved in the synthesis of raw material for cell proliferation, in both prokaryotic and eukaryotic cells
We have to mention pyrimethamine and proguanil as antimalarial drugs [4,5]; trimethoprim, an antibacterial drug commonly used in association with sulfonamides, like sulfamethoxazole [6,7]; and methotrexate, the first-in-class anti-cancer agent acting via DHFR inhibition [8,9]

Summary

Introduction

Since the middle of the last century, the potential of the dihydrofolate reductase (DHFR) enzyme as a therapeutic target for treating infections has been evidenced [1,2]. (THF),which whichisis activeper perse, se, but but itit isis the the precursor precursor of of the the active active form form known known as essential for the de novo synthesis of purines, amino acids, and thymidylate (TMP). The structure of the human DHFR in complex with NADPH and with the human in complex with and with the antifolate antifolate 6-([5-quinolylamino]methyl)-2,4-diamino-5-methylpyrido[2,3-d]pyrimidine (PDB ID: 1KMS). 6-([5-quinolylamino]methyl)-2,4-diamino-5-methylpyrido[2,3-d]pyrimidine (PDB ID: 1KMS) has been elucidated (Figure 3) [21], allowing the foundation for the ad hoc design of compounds targeting hDHFR. 2. Synthetic pathway metabolism.DHFR catalyzes the passage of a hydride cofactor nicotinamide adenine dinucleotide phosphate (NADPH), used as an electron donor, to the cofactor nicotinamide adenine dinucleotide phosphate (NADPH), used as an electron donor, dihydrofolate (DHF), through a protonation to produce tetrahydrofolate (THF).

Relevance

Inhibitors of Bovine DHFR

Chemical

11. Natural

New Strategies in DHFR Drug Discovery

Findings

Conclusions