The Nitric Oxide Prodrug V-PROLI/NO Inhibits Cellular Uptake of Proline

作者：Hong Sam Y; Borchert Gregory L; Maciag Anna E; Nandurdikar Rahul S; Saavedra Joseph E; Keefer Larry K; Phang James M^*; Chakrapani Harinath

来源：ACS Medicinal Chemistry Letters, 2010, 1(8): 386-389.

DOI：10.1021/ml1000905

• Nitric oxide
• prodrug
• proline
• transporter
• PROLI/NO-V-PROLI/NO

V-PYRRO/NO is a well-studied nitric oxide (NO) prodrug that has been shown to protect human liver cells from arsenic, acetaminophen, and other toxic assaults in vivo. Its proline based analogue, V-PROLI/NO, was designed to be a more biocompatible form that decomposes to the naturally occurring metabolites of proline, NO, and glycolaldehyde. Like V-PYRRO/NO, this cytochrome P450-activated prodrug was previously assumed to passively diffuse through the cellular membrane. Using (14)C-labeled proline in a competition assay, we show that V-PROLI/NO is transported through proline transporters into multiple cell lines. a fluorescent NO-sensitive dye (DAF-FM diacetate) and nitrite excretion indicated elevated intracellular NO release after metabolism over V-PYRRO/NO. These results also allowed us to predict and design a more permeable analogue, V-SARCO/NO. We report a proline transporter based strategy for the selective transport of NO prodrugs that may have enhanced and aid in the development of further NO prodrugs with increased permeability.

• 出版日期2010-11