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

  1. Author:
    Hong, S. Y.
    Borchert, G. L.
    Maciag, A. E.
    Nandurdikar, R. S.
    Saavedra, J. E.
    Keefer, L. K.
    Phang, J. M.
    Chakrapani, H.

  2. Author Address

    [Phang, James M.] NCI, Metab & Canc Susceptibil Sect, Frederick, MD 21702 USA. [Hong, Sam Y.; Nandurdikar, Rahul S.; Keefer, Larry K.] SAIC Frederick, Comparat Carcinogenesis Lab, Chem Sect, Frederick, MD 21702 USA. [Borchert, Gregory L.; Maciag, Anna E.; Saavedra, Joseph E.] SAIC Frederick, Basic Sci Program, Frederick, MD 21702 USA. [Chakrapani, Harinath] Indian Inst Sci Educ & Res, Dept Chem, Pune 411008, Maharashtra, India.;Phang, JM, NCI, Metab & Canc Susceptibil Sect, Frederick, MD 21702 USA.;phangj@mail.nih.gov harinath@iiserpune.ac.in
    1. Year: 2010
    2. Date: Nov
  2. Journal: Acs Medicinal Chemistry Letters
    1. 1
    2. 8
    3. Pages: 386-389
  4. Type of Article: Article
  5. ISSN: 1948-5875
  1. Abstract:

    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 C-14-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.

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External Sources

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  2. DOI: 10.1021/ml1000905
  3. View record in Web of Science®
  4. WOS: 000284203100004

Library Notes

  1. Fiscal Year: FY2010-2011
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