Effect of alkyl group on transnitrosation of N-nitrosothiazolidine thiocarboxamides

[Display omitted] 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-nitrosothio-proline analogue, exhibited a high GSNO formation activity. In this stud...

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Published in:Bioorganic & medicinal chemistry 2015-10, Vol.23 (20), p.6733-6739
Main Authors: Inami, Keiko, Ono, Yuta, Kondo, Sonoe, Nakanishi, Ikuo, Ohkubo, Kei, Fukuzumi, Shunichi, Mochizuki, Masataka
Format: Article
Language:English
Subjects:
1,3-Thiazolidine
Hydrogen-Ion Concentration
Kinetics
Molecular Structure
N-Nitrosothioproline
Nitrosation
Nitroso Compounds - chemical synthesis
Nitroso Compounds - chemistry
Quantum Theory
S-Nitrosoglutathione
Thiazoles - chemical synthesis
Thiazoles - chemistry
Thiazolidines - chemical synthesis
Thiazolidines - chemistry
Thiocarboxamide
Transnitrosation
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Summary:[Display omitted] 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-nitrosothio-proline 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 followed the order 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 sulfur 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 sulfur atom in the thioamide group. Finally, the nitroso group is transferred to GSH to form GSNO.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2015.09.008