Alkyl cinnamates as regulator for the C1 domain of protein kinase C isoforms

The protein kinase C (PKC) family of serine/threonine kinases is an attractive drug target for the treatment of cancer and other diseases. Natural product curcumin is known to interact with PKC isoforms through the C1 domain and modulate PKC activity. The reported results demonstrate that the symmetric curcumin molecule might act as two separate units during its recognition of C1 domains. To understand the importance of the two halves of curcumin in PKC binding and to develop effective PKC regulators, we synthesized a series of alkyl cinnamates (1–8), characterized absorption and fluorescence properties and measured binding affinities with the C1b subdomains of PKC isoforms. The binding parameters of the monomeric compounds and liposomes containing compounds confirmed their interaction with the C1b subdomains of PKCδ and PKCθ. The molecular docking analysis with PKCδ and PKCθ C1b subdomains revealed that the alkyl cinnamates form hydrogen bond with the backbone of the protein at the same binding site as that of diacylglycerol and phorbol esters. The results show that the alkyl cinnamates bind to the activator binding site of PKCs and both methoxy and hydroxyl groups play important roles in the binding process.

Long chain alkyl cinnamates show interaction with the C1b subdomain of PKC isoforms through the diacylglycerol (DAG) or phorbol ester binding site and forms hydrogen bonds with the residues at the activator binding site.Figure optionsDownload as PowerPoint slideHighlights
► Long chain alkyl cinnamates were synthesized.
► Absorption and fluorescence properties of the alkyl cinnamates were characterized.
► Interactions of alkyl cinnamates with the C1b subdomains of PKC isoforms were analyzed by fluorescence based techniques.
► The results reveal the binding of alkyl cinnamates to C1b subdomains through the diacylglycerol/phorbol ester binding site.