Synthesis of a novel cyclic prodrug of S-allyl-glutathione able to attenuate LPS-induced ROS production through the inhibition of MAPK pathways in U937 cells.
A novel cyclic prodrug of S-allyl-glutathione (CP11), obtained by using an acyloxy-alkoxy linker, was estimated for its pharmacokinetic and biological properties. The stability of CP11 was evaluated at pH 1.2, 7.4, in simulated fluids with different concentrations of enzymes, and in human plasma. The anti-inflammatory ability of CP11 was assessed in U937 cells, an immortalized human monocyte cell line. Results showed that CP11 is stable at acidic pH showing a possible advantage for oral delivery due to the longer permanence in the stomach. Having a permeability coefficient of 2.49 × 10(-6) cm s(-1), it was classified as discrete BBB-permeable compound. Biological studies revealed that CP11 is able to modulate inflammation mediated by LPS in U937 cells preventing the increase of ROS intracellular levels through interaction with the MAPK pathway.
Department of Pharmacy and †Department of Medicine and Aging Science, University "G. D'Annunzio" , Via dei Vestini 31, 66100 Chieti, Italy.
Antonia
A
Patruno
Erika
E
Fornasari
Antonio
A
Di Stefano
Laura S
LS
Cerasa
Lisa
L
Marinelli
Leonardo
L
Baldassarre
Piera
P
Sozio
Hasan
H
Turkez
Sara
S
Franceschelli
Alessio
A
Ferrone
Viviana
V
Di Giacomo
Lorenza
L
Speranza
Mario
M
Felaco
Ivana
I
Cacciatore
D002463:Cell Membrane Permeability; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry*; D005978:Glutathione / Q000138:chemical synthesis* / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008070:Lipopolysaccharides / Q000737:chemistry; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008956:Models, Chemical; D009000:Monocytes / Q000166:cytology; D010539:Permeability; D011355:Prodrugs / Q000737:chemistry*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013696:Temperature; D020298:U937 Cells
D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D011355:Prodrugs; D017382:Reactive Oxygen Species; D005978:Glutathione
MAPK pathway; acyloxy-alkoxy linker; cyclic prodrug; glutathione