Synthesis, modeling, and in vitro activity of (3'S)-epi-K-252a analogues. Elucidating the stereochemical requirements of the 3'-sugar alcohol on trkA tyrosine kinase activity.
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.
Gingrich
Diane E
DE
Department of Medicinal Chemistry, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380, USA.
Yang
Shi X
SX
Gessner
George W
GW
Angeles
Thelma S
TS
Hudkins
Robert L
RL
D000818:Animals; D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D026121:Indole Alkaloids; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D020917:Receptor, trkA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013402:Sugar Alcohols / Q000737:chemistry*; D013816:Thermodynamics
D002227:Carbazoles; D026121:Indole Alkaloids; D013402:Sugar Alcohols; C049985:staurosporine aglycone; D020917:Receptor, trkA; D011493:Protein Kinase C