title: Macrocyclic diacylglycerol-bis-lactones as conformationally constrained analogues of diacylglycerol-lactones. Interactions with protein kinase C.
abstract: A series of macrocyclic diacylglycerol (DAG)-bis-lactones were investigated as extreme conformationally constrained analogues of DAG-lactones in order to seek more potent protein kinase C (PKC) ligands with higher binding affinities and less lipophilicity than previous compounds. The additional constraint achieved the desired objective as exemplified by the macrocyclic DAG-bis-lactone 57, which exhibited a 6-fold higher binding affinity for PKCalpha (K(i) = 6.07 nM) than the corresponding nonmacrocyclic 3-alkylidene DAG-lactone 6. A structure-activity relationship (SAR) analysis of the macrocyclic DAG-bis-lactones demonstrated a parabolic relationship between activity and lipophilicity, as well as a predilection for the Z-alkylidene isomers as the preferred ligands. Molecular docking studies revealed that macrocyclic DAG-bis-lactone 57 bound to the C1b domain of PKCalpha exclusively in the sn-1 binding mode in contrast to DAG-lactone 6, which showed both sn-1 and sn-2 binding modes. It is proposed that the high potency displayed by these macrocyclic DAG-bis-lactones results from a set of more favorable hydrogen bonding and hydrophobic interactions with PKCalpha as well as from a reduced entropy penalty due to conformational restriction.
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Shinlim-Dong, Kwanak-Ku, Seoul 151-742, Korea.
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Kang
authors.forename: Su Yeon
authors.initials: SY
authors.lastname: Kim
authors.forename: Jeewoo
authors.initials: J
authors.lastname: Lee
authors.forename: Victor E
authors.initials: VE
authors.lastname: Marquez
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Lewin
authors.forename: Larry V
authors.initials: LV
authors.lastname: Pearce
authors.forename: Peter M
authors.initials: PM
authors.lastname: Blumberg
mesh_terms: D004075:Diglycerides / Q000138:chemical synthesis* / Q000737:chemistry; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D011493:Protein Kinase C / Q000737:chemistry*
chemical_list: D004075:Diglycerides; D007783:Lactones; D008024:Ligands; D011493:Protein Kinase C