Can. J. Chem. 66, 2751(1988. 5,s-Diphenylhydanytoin (phenytoin) is the most widely used anticonvulsant drug, but has many side effects. Although its chemical mode of action is unknown, phenytoin is believed to function primarily by interference with the transport of sodium ions across the neuronal membrane. Structure-activity and lipophilicity-activity studies suggest that the drug interacts with its receptor through hydrogen bonding to the N3-C4 amide bond, and an aromatic-aromatic interaction with the C5 substituent. Since sodium channels are cysteine-rich peptides, whose function depends upon the cysteineecystine redox process, it has been hypothesized that the action of the phenytoin receptor may be mimicked by a properly designed cyclodepsipeptide containing a cystinyl moiety, a cavity lined with five oxygen atoms oriented in the trigonal-bipyramidal manner appropriate for selective transport of sodium ions, and a site for the binding of phenytoin. A computer programme and strategy were developed to permit the three-dimensional structures of potential target molecules to be viewed, prior to synthesis. Use of this programme led to the discovery of Boc-~-cystinyl-glycyI-~-prolyl-glycyl-~-prolyl-~-cystine-OCHPh. This compound, termed phenceptin, was synthesized from a linear precursor containing tert-butoxycarbonyl protection at the N-terminus, benzhydryl ester protection at the C-terminus, and trityl protection at sulfur. Detritylation and cyclization to phenceptin were accomplished with iodine in methanol-pyridine. Using an n-octanol membrane to study the kinetics of ion transport, phenceptin was found to transport sodium ions selectively, but only in its oxidized, cyclic form. This transport was inhibited significantly by one mol-equiv. of phenytoin, and not at all by biologically inactive analogs of the drug. The nature of the binding of phenytoin to phenceptin was examined by nuclear magnetic resonance, in n-CsD17-OH solvent, and found to involve hydrogen bonding of the drug to a glycine residue whose oxygen atom is involved in complexation to sodium ions. SAUL WOLFE, RAYMOND JOHN BOWERS, HEE-SOOK SHIN, CHANG-KOOK SOHN, DONALD FREDRIC WEAVER ET KIYULLYANG. Can. J. Chem. 66, 2751 (1988). La diphCnyl-5,s hydantoyne (phtnytoi'ne) est le mtdicament le plus utilist comme anticonvulsivant; toutefois, il provoque de nombreuses rkactions secondaires. MCme si son mode d'action chimique est inconnu, on croit que la phtnytoi'ne agit principalement par interftrence avec le transport des ions sodium a travers les membranes neuronales. Des etudes de structure/activitC et caractere liphophilique/activitt suggkrent que la drogue interagit avec son rtcepteur par le biais de liaisons hydrogknes avec la liaison amide N3-C4 et par une interaction aromatique/aromatique avec le substituant en C5. Puisque les canaux du sodium sont des peptides riches en cysttine dont la fonction dtpend du processus redox cysteine/cystine, il a Ct C suggCrC que l'on pourrait rCpliquer l'action du rCcepteur de la phCnytoi'ne a l'aide d'un cyclod...
In this work, the reactions of carbamyl and thiocarbamyl halides with NH 3 were studied in the gas phase at the MP2(FC)/6-31+G(d) level of theory. Single point calculations were performed at the QCISD/6-311+G(3df,2p) to refine the energetics. The reaction mechanisms were also studied in aqueous solution. The structures were fully optimized at the CPCM-MP2(FC)/6-31+G(d) and refined by a single point CPCM-QCISD/6-311+G(3df,2p) calculations. The reaction mechanisms for the title compounds were compared with those for the acetyl and thioacetyl halides. The lower reactivity of carbamyl (and thiocarbamyl) groups was explained by comparing the C=O and C=S π-bond strengths as well as resonance contributions in the ground state.
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