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dc.contributor.authorYuan, Hushan
dc.contributor.authorPupo, Monica T.
dc.contributor.authorBlois, Joe
dc.contributor.authorSmith, Adam
dc.contributor.authorWeissleder, Ralph
dc.contributor.authorClardy, Jon
dc.contributor.authorJosephson, Lee
dc.date.accessioned2019-09-21T03:36:52Z
dc.date.issued2009
dc.identifier.citationYuan, Hushan, Monica T. Pupo, Joe Blois, Adam Smith, Ralph Weissleder, Jon Clardy, and Lee Josephson. 2009. “A Stabilized Demethoxyviridin Derivative Inhibits PI3 Kinase.” Bioorganic & Medicinal Chemistry Letters 19 (15): 4223–27. https://doi.org/10.1016/j.bmcl.2009.05.105.
dc.identifier.issn0960-894X
dc.identifier.issn1464-3405
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:41384322*
dc.description.abstractThe viridins like demethoxyviridin (Dmv) and wortmannin (Wm) are nanomolar inhibitors of the PI3 kinases, a family of enzymes that play key roles in a host of regulatory processes. Central to the use of these compounds to investigate the role of PI3 kinase in biological systems, or as scaffolds for drug development, are the interrelated issues of stability, chemical reactivity, and bioactivity as inhibitors of PI3 kinase. We found that Dmv was an even more potent inhibitor of PI3 kinase than Wm. However, Dmv was notably less stable than Wm in PBS, with a half-life of 26 min versus Wm's half-life of 3470 min. Dmv, like Wm, disappeared in culture media with a half-life of less than 1 min. To overcome Dmv's instability, it was esterified at the C1 position, and then reacted with glycine at the C20 position. The resulting Dmv derivative, termed SA-DmvC20-Gly had a half-life of 218 min in PBS and 64 min in culture media. SA-DmvC20-Gly underwent an exchange reaction at the C20 position with N-acetyl lysine in a manner similar to a WmC20 derivative, WmC20-Proline. SA-DmvC20-Gly inhibited PI3 kinase with an IC(50) of 44 nM, compared to Wm's IC(50) of 12 nM. These results indicate that the stability of Dmv can be manipulated by reactions at the C1 and C20 positions, while substantially maintaining its ability to inhibit PI3 kinase. Our results indicate it may be possible to obtain stabilized Dmv derivatives for use as PI3 kinase inhibitors in biological systems.
dc.language.isoen_US
dc.publisherElsevier
dash.licenseLAA
dc.titleA Stabilized Demethoxyviridin Derivative Inhibits PI3 kinase
dc.typeJournal Article
dc.description.versionAccepted Manuscript
dc.relation.journalBioorganic & Medicinal Chemistry Letters
dash.depositing.authorWeissleder, Ralph::ea07ce19f187d4fab47c56ee97fa5c5a::600
dc.date.available2019-09-21T03:36:52Z
dash.workflow.comments1Science Serial ID 14873
dc.identifier.doi10.1016/j.bmcl.2009.05.105
dash.source.volume19;15
dash.source.page4223


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