Conformationally constrained analogues of diacylglycerol (DAG). Effect on protein kinase C (PK-C) binding by the isosteric replacement of sn-1 and sn-2 esters in DAG-lactones.
In order to determine the importance of the two ester pharmacophores in high affinity, conformationally constrained DAG-lactones (Lac-1-5) as PK-C ligands, we have independently replaced the sn-1 and sn-2 carbonyl esters in these compounds by ketone (2, 10, 11), amide (3, 25-28), and hydroxyl (12, 13) isosteres. Although the ketone analogue of the sn-1 ester (2) exhibited comparable activity to the parent Lac-1 when taking into account the difference in lipophilicities, the other isosteres were significantly poorer PK-C alpha ligands compared to the parent DAG-lactones. This study demonstrates that the ester functionality in DAG-lactone plays an important role in the ligand's capacity to form a strong hydrogen bond with Gly253 at the active site. The discrete K(i) analysis from the sn-1 and sn-2 isosteres further confirms that the DAG-lactones bind preferentially to the C1-domain in the sn-2 binding mode, as previously suggested.
Kang
Ji-Hye
JH
Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
Chung
Hye-Eun
HE
Kim
Su Yeon
SY
Kim
Yerim
Y
Lee
Jeewoo
J
Lewin
Nancy E
NE
Pearce
Larry V
LV
Blumberg
Peter M
PM
Marquez
Victor E
VE
D000577:Amides / Q000737:chemistry / Q000378:metabolism; D004075:Diglycerides / Q000737:chemistry* / Q000378:metabolism*; D004952:Esters / Q000737:chemistry / Q000378:metabolism; D006860:Hydrogen Bonding; D007536:Isomerism; D007783:Lactones / Q000737:chemistry* / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D011493:Protein Kinase C / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
D000577:Amides; D004075:Diglycerides; D004952:Esters; D007783:Lactones; D008024:Ligands; D011994:Recombinant Proteins; D011493:Protein Kinase C