TY - JOUR
T1 - Galactosyl derivatives of L-arginine and D-arginine
T2 - Synthesis, stability, cell permeation, and nitric oxide production in pituitary GH3 cells
AU - Melisi, Daniela
AU - Secondo, Agnese
AU - Montoro, Paola
AU - Piacente, Sonia
AU - Rimoli, Maria Grazia
AU - Minale, Massimiliano
AU - De Caprariis, Paolo
AU - Annunziato, Lucio
PY - 2006/8/10
Y1 - 2006/8/10
N2 - 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.
AB - 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.
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U2 - 10.1021/jm060005s
DO - 10.1021/jm060005s
M3 - Article
C2 - 16884294
AN - SCOPUS:33746896200
VL - 49
SP - 4826
EP - 4833
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 16
ER -