Journal Article Effect of Alkyl Group on Transnitrosation of N-Nitrosothiazolidine Thiocarboxamides

Inami, Keiko  ,  Ono, Yuta  ,  Kondo, Sonoe  ,  Nakanishi, Ikuo  ,  Ohkubo, Kei  ,  Fukuzumi, Shunichi  ,  Mochizuki, Masataka

23 ( 20 )  , pp.6733 - 6739 , 2015-09 , Elsevier
S-Nitrosoglutathione (GSNO) relaxes vascular smooth muscles, prevents platelet aggregation, and acts as a potential in vivo nitric oxide donor. 3-Nitroso-1,3-thiazolidine- 4-thiocarboxamide (1), a N-nitrosothioproline analogue, exhibited a high GSNO formation activity. In this study, two compounds (2 and 3) based on compound 1 were newly synthesized by introducing either one or two methyl groups onto a nitrogen atom on the thioamide substituent in 1. The pseudo-first-order rate constants (kobs) for the GSNO formation for the reaction between the compound and glutathione (GSH) followed the orde 1 > 2 ≈ 3. Thus, the introduction of a methyl group(s) onto the thioamide group led to a decrease in the transnitrosation activity. On the basis of density functional theoretical calculations, the transnitrosation for the N-nitrosothiazolidine thiocarboxamides was proposed to proceed via a bridged intermediate pathway. Specifically, the protonated compound 1 forms a bridged structure between the nitrogen atom in the nitroso group and two sulphur atoms–one in the ring and the other in the substituent. The bridged intermediate gives rise to a second intermediate, in which the nitroso group is bonded to the sulphur atom in the thioamide group. Finally, the nitroso group is transferred to GSH to form GSNO.

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