Galactosyl derivatives of L-arginine and D-arginine: Synthesis, stability, cell permeation, and nitric oxide production in pituitary GH3 cells

Daniela Melisi, Agnese Secondo, Paola Montoro, Sonia Piacente, Maria Grazia Rimoli, Massimiliano Minale, Paolo De Caprariis, Lucio Annunziato

Research output: Contribution to journalArticlepeer-review

Abstract

Nitric oxide (NO) is critical for the normal physiological regulation of the nervous system and other tissues. L-Arginine, but not D-arginine, is the natural substrate for nitric oxide synthase (NOS), for it is enzymatically converted to NO and L-citrulline. However, recent evidence suggests that D-arginine can also produce NO and NO-derivatives via a different pathway. The aim of the present paper was to raise NO levels in the cells by increasing the cell permeation of its precursors. To this aim, two galactosyl prodrugs, L-arginine-D-galactos-6′-yl ester (L-ArgGal) and D-arginine-D-galactos- 6′-yl ester (D-ArgGal) were synthesized. Remarkably, using the HPLC-ESI/MS technique, we found that L-ArgGal and D-ArgGal prodrugs both increased the concentration levels of L- and D-arginine and their derivatives in pituitary GH3 cells. Furthermore, we found that D-ArgGal (1) penetrated cell membranes more rapidly than its precursor D-arginine, (2) released arginine more slowly and in greater amounts than L-ArgGal, and (3) produced much higher levels of DAF-2 monitored NO and nitrite than did L-ArgGal under the same experimental conditions. In conclusion, these results indicate that an increase in the cell permeation of L- and D-arginine by L-ArgGal and D-ArgGal can lead to an increase in NO levels.

Original languageEnglish
Pages (from-to)4826-4833
Number of pages8
JournalJournal of Medicinal Chemistry
Volume49
Issue number16
DOIs
Publication statusPublished - Aug 10 2006

ASJC Scopus subject areas

  • Organic Chemistry

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