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Article

Esterase-Sensitive Prodrugs of a Potent Bisubstrate Inhibitor of Nicotinamide N-Methyltransferase (NNMT) Display Cellular Activity

1
Biological Chemistry Group, Institute of Biology Leiden, Leiden University, Sylviusweg 72, 2333 BE Leiden, The Netherlands
2
Department of Clinical Sciences, Universitá Politecnica delle Marche, Via Ranieri 65, 60131 Ancona, Italy
3
Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland
4
Faculty of Medicine, Chair of Pharmacology, Jagiellonian University Medical College, Grzegorzecka 16, 31-531 Krakow, Poland
5
Central Diagnostic Laboratory, Division Laboratories, Pharmacy and Biomedical Genetics (LAB), Universitair Medisch Centrum Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Nuno Vale
Biomolecules 2021, 11(9), 1357; https://doi.org/10.3390/biom11091357
Received: 13 August 2021 / Revised: 3 September 2021 / Accepted: 10 September 2021 / Published: 14 September 2021
(This article belongs to the Special Issue Functions of Nicotinamide N-Methyltransferase in Cancer)
A recently discovered bisubstrate inhibitor of Nicotinamide N-methyltransferase (NNMT) was found to be highly potent in biochemical assays with a single digit nanomolar IC50 value but lacking in cellular activity. We, here, report a prodrug strategy designed to translate the observed potent biochemical inhibitory activity of this inhibitor into strong cellular activity. This prodrug strategy relies on the temporary protection of the amine and carboxylic acid moieties of the highly polar amino acid side chain present in the bisubstrate inhibitor. The modification of the carboxylic acid into a range of esters in the absence or presence of a trimethyl-lock (TML) amine protecting group yielded a range of candidate prodrugs. Based on the stability in an aqueous buffer, and the confirmed esterase-dependent conversion to the parent compound, the isopropyl ester was selected as the preferred acid prodrug. The isopropyl ester and isopropyl ester-TML prodrugs exhibit improved cell permeability, which also translates to significantly enhanced cellular activity as established using assays designed to measure the enzymatic activity of NNMT in live cells. View Full-Text
Keywords: NNMT; inhibition; prodrug; cell permeability; esterase; cellular activity NNMT; inhibition; prodrug; cell permeability; esterase; cellular activity
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MDPI and ACS Style

van Haren, M.J.; Gao, Y.; Buijs, N.; Campagna, R.; Sartini, D.; Emanuelli, M.; Mateuszuk, L.; Kij, A.; Chlopicki, S.; Escudé Martinez de Castilla, P.; Schiffelers, R.; Martin, N.I. Esterase-Sensitive Prodrugs of a Potent Bisubstrate Inhibitor of Nicotinamide N-Methyltransferase (NNMT) Display Cellular Activity. Biomolecules 2021, 11, 1357. https://doi.org/10.3390/biom11091357

AMA Style

van Haren MJ, Gao Y, Buijs N, Campagna R, Sartini D, Emanuelli M, Mateuszuk L, Kij A, Chlopicki S, Escudé Martinez de Castilla P, Schiffelers R, Martin NI. Esterase-Sensitive Prodrugs of a Potent Bisubstrate Inhibitor of Nicotinamide N-Methyltransferase (NNMT) Display Cellular Activity. Biomolecules. 2021; 11(9):1357. https://doi.org/10.3390/biom11091357

Chicago/Turabian Style

van Haren, Matthijs J., Yongzhi Gao, Ned Buijs, Roberto Campagna, Davide Sartini, Monica Emanuelli, Lukasz Mateuszuk, Agnieszka Kij, Stefan Chlopicki, Pol Escudé Martinez de Castilla, Raymond Schiffelers, and Nathaniel I. Martin. 2021. "Esterase-Sensitive Prodrugs of a Potent Bisubstrate Inhibitor of Nicotinamide N-Methyltransferase (NNMT) Display Cellular Activity" Biomolecules 11, no. 9: 1357. https://doi.org/10.3390/biom11091357

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