Macrocyclic diacylglycerol-bis-lactones as conformationally constrained analogues of diacylglycerol-lactones. Interactions with protein kinase C.

ID: ALA1138662

Journal: J Med Chem

Title: Macrocyclic diacylglycerol-bis-lactones as conformationally constrained analogues of diacylglycerol-lactones. Interactions with protein kinase C.

Authors: Kang JH, Kim SY, Lee J, Marquez VE, Lewin NE, Pearce LV, Blumberg PM.

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.

CiteXplore: 15267238

DOI: 10.1021/jm0497747

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