| Autor: |
Gingrich DE; Department of Medicinal Chemistry, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380, USA., Yang SX, Gessner GW, Angeles TS, Hudkins RL |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2005 Jun 02; Vol. 48 (11), pp. 3776-83. |
| DOI: |
10.1021/jm040178m |
| Abstrakt: |
Utilizing our recently published semisynthetic approach to the (3'S)-K-252a diastereomer, we report the first synthesis of the (3'R)-10 diastereomer and a set of related epimers, with the goal of defining the stereochemical role of the 3'-sugar hydroxyl group on trkA tyrosine kinase activity and selectivity. (3'R)-10 displayed potent trkA inhibitory activity with an IC50 value of 4 nM. The corresponding deshydroxy epimer (3'S)-14 was 7-fold more potent than its 3'R counterpart (natural stereochemistry) with a trkA IC50 value of 3 nM and demonstrated >280-fold selectivity over PKC (IC50 = 850 nM). In cells, (3'S)-14 displayed potent inhibition of trkA autophosphorylation with an IC50 < 10 nM. Molecular modeling studies revealed that the 3'-OH, due to the inverted geometry, forms significant H-bonding interactions with Glu27 and Arg195, an interaction that is not attainable with the natural isomers. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
|
