98045-03-5Relevant articles and documents
Esterase-sensitive prodrugs of a potent bisubstrate inhibitor of nicotinamide n-methyltransferase (Nnmt) display cellular activity
van Haren, Matthijs J.,Gao, Yongzhi,Buijs, Ned,Campagna, Roberto,Sartini, Davide,Emanuelli, Monica,Mateuszuk, Lukasz,Kij, Agnieszka,Chlopicki, Stefan,de Castilla, Pol Escudé Martinez,Schiffelers, Raymond,Martin, Nathaniel I.
, (2021/09/16)
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.
Synthesis of triazole cages containing C3-symmetric α-cyclic tripeptide scaffold
Chakraborty, Subrata,Tai, Dar-Fu
, p. 2274 - 2276 (2014/04/17)
Two water-soluble C3-symmetric 1,2,3-triazole cages containing α-cyclic tripeptide were efficiently synthesized. The key steps include a click reaction to incorporate l-glutamic or l-aspartic acids to a tripodal linker and a unique one-pot cyclotrimerization.
Structure-guided design of α-amino acid-derived Pin1 inhibitors
Potter, Andrew J.,Ray, Stuart,Gueritz, Louisa,Nunns, Claire L.,Bryant, Christopher J.,Scrace, Simon F.,Matassova, Natalia,Baker, Lisa,Dokurno, Pawel,Robinson, David A.,Surgenor, Allan E.,Davis, Ben,Murray, James B.,Richardson, Christine M.,Moore, Jonathan D.
scheme or table, p. 586 - 590 (2010/04/26)
The peptidyl prolyl cis/trans isomerase Pin1 is a promising molecular target for anti-cancer therapeutics. Here we report the structure-guided evolution of an indole 2-carboxylic acid fragment hit into a series of α-benzimidazolyl-substituted amino acids.
