Synthesis and in silico evaluation of novel uridyl sulfamoylbenzoate derivatives as potential anticancer agents targeting M1 subunit of human ribonucleotide reductase (hRRM1)

Ribonucleotide reductase (RNR) is a key target in cancer chemotherapy. The enzyme catalyzes reduction of ribonucleotides to 2 '-deoxyribonucleotides and its activity is rate-limiting in de novo synthesis of deoxynucleotide triphosphates (dNTPs). Nucleoside analogues have been investigated as anticancer drugs that inhibit human RNR, however, problems with toxicity and cancer resistance remain challenging. Herein we report a convenient synthesis of six novel nucleoside analogues modified with benzenesulfonamide derivatives: 4-carboxybenzenesulfonamide, 4-chloro-3-sulfamoylbenzoic acid, 2-chloro-4-fluoro-5-sulfamoylbenzoic acid, 2,3-dimethoxy-5-sulfamoylbenzoic acid, N-benzyl-4-chloro-5-sulfamoylanthranilic acid, or furosemide. Mitsunobu reaction between the carboxyl group of benzoic acid sulfonamides and the 5 ' hydroxyl of uridine produced uridyl sulfamoylbenzoates with excellent yields. Molecular docking was performed to examine conformation and binding affinity with the large subunit M1 of RNR. The sulfamoyl moiety has shown strong H-bonding with known substrate-binding residues such as Ser202 and Thr607 in the catalytic site. The electron-withdrawing fluorine and chlorine enhanced binding, whereas the electron-donating methoxy group diminished binding. In silico ADMET evaluations showed favorable pharmacological and toxicity profiles with excellent solubility scores of at least -3.0 log S. Hence, we propose sulfamoylbenzoate nucleosides enhanced with electron-withdrawing groups as potential RNR inhibitors and are worth further investigation as RNR-targeted anticancer drugs.

Automated summary

A convenient synthesis method for six nucleoside analogues modified with benzenesulfonamide derivatives was reported. The molecular docking experiments showed that these analogues, enhanced with electron-withdrawing groups, have potential as ribonucleotide reductase inhibitors with favorable pharmacological and toxicity profiles.