A stabilized demethoxyviridin derivative inhibits PI3 kinase |
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Authors: | Hushan Yuan Monica T Pupo Joe Blois Adam Smith Ralph Weissleder Jon Clardy Lee Josephson |
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Institution: | 1. Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, MA 02129, United States;2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115, United States;3. Universidade de Sao Paulo, Ribeirao Preto, SP, Brazil;4. Center for Systems Biology, Massachusetts General Hospital and Department of Systems Biology, Harvard Medical School, 185 Cambridge Street, Boston, MA 02115, United States |
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Abstract: | The 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 IC50 of 44 nM, compared to Wm’s IC50 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. |
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