Effect of alkyl group on transnitrosation of N-nitrosothiazolidine thiocarboxamides

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)6733-6739
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume23
Issue number20
DOIs
StatePublished - 15 Oct 2015

Bibliographical note

Publisher Copyright:
© 2015 Elsevier Ltd. All Rights Reserved.

Keywords

  • 1,3-Thiazolidine
  • N-Nitrosothioproline
  • S-Nitrosoglutathione
  • Thiocarboxamide
  • Transnitrosation

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