Igor V Komarov1, Aleksandr Yu Ishchenko2, Aleksandr Hovtvianitsa3, Viacheslav Stepanenko4, Serhii Kharchenko5, Andrew D Bond6, Anthony J Kirby7. 1. Institute of High Technologies, Taras Shevchenko National University of Kyiv, Vul. Volodymyrska 64/13, 01601 Kyiv, Ukraine. ik214@yahoo.com. 2. Enamine Ltd., Vul. Chervonotkatska 78, 02094 Kyiv, Ukraine. ischa1986@ukr.net. 3. Enamine Ltd., Vul. Chervonotkatska 78, 02094 Kyiv, Ukraine. cayenestar@gmail.com. 4. Enamine Ltd., Vul. Chervonotkatska 78, 02094 Kyiv, Ukraine. v.stepanenko@enamine.net. 5. Enamine Ltd., Vul. Chervonotkatska 78, 02094 Kyiv, Ukraine. serxioharchenko@ukr.net. 6. University Chemical Laboratory, Cambridge CB2 1EW, UK. adb29@cam.ac.uk. 7. University Chemical Laboratory, Cambridge CB2 1EW, UK. ajk1@cam.ac.uk.
Abstract
Unconstrained amides that undergo fast hydrolysis under mild conditions are valuable sources of information about how amide bonds may be activated in enzymatic transformations. We report a compound possessing an unconstrained amide bond surrounded by an amino and a carboxyl group, each mounted in close proximity on a bicyclic scaffold. Fast amide hydrolysis of this model compound was found to depend on the presence of both the amino and carboxyl functions, and to involve a proton transfer in the rate-limiting step. Possible mechanisms for the hydrolytic cleavage and their relevance to peptide bond cleavage catalyzed by natural enzymes are discussed. Experimental observations suggest that the most probable mechanisms of the model compound hydrolysis might include a twisted amide intermediate and a rate-determining proton transfer.
Unconstrained amides that undergo fast hydrolysis under mild conditions are valuable sources of information about how n class="Chemical">amide bonds may be activated in enzymatic transformations. We report a compound possessing an unconstrained amide bond surrounded by an amino and a carboxyl group, each mounted in close proximity on a bicyclic scaffold. Fast amide hydrolysis of this model compound was found to depend on the presence of both the amino and carboxyl functions, and to involve a proton transfer in the rate-limiting step. Possible mechanisms for the hydrolytic cleavage and their relevance to peptide bond cleavage catalyzed by natural enzymes are discussed. Experimental observations suggest that the most probable mechanisms of the model compound hydrolysis might include a twisted amide intermediate and a rate-determining proton transfer.
Authors: Lixin Wang; Yunmei Song; Ankit Parikh; Paul Joyce; Rosa Chung; Liang Liu; Franklin Afinjuomo; John D Hayball; Nikolai Petrovsky; Thomas G Barclay; Sanjay Garg Journal: Pharmaceutics Date: 2019-11-06 Impact factor: 6.321