title: Alkyl cinnamates as regulator for the C1 domain of protein kinase C isoforms.
abstract: 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.
authors.affiliation: Department of Chemistry, Indian Institute of Technology Guwahati, North Guwahati, Assam, India.
authors.forename: Narsimha
authors.initials: N
authors.lastname: Mamidi
authors.forename: Sukhamoy
authors.initials: S
authors.lastname: Gorai
authors.forename: Jashobanta
authors.initials: J
authors.lastname: Sahoo
authors.forename: Debasis
authors.initials: D
authors.lastname: Manna
mesh_terms: D000478:Alkylation; D000818:Animals; D001665:Binding Sites; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002934:Cinnamates / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D004075:Diglycerides / Q000378:metabolism; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D005454:Fluorescence Polarization; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008081:Liposomes / Q000378:metabolism; D008958:Models, Molecular; D010703:Phorbol Esters / Q000378:metabolism; D011493:Protein Kinase C / Q000737:chemistry* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D012995:Solubility
chemical_list: D002934:Cinnamates; D004075:Diglycerides; D007527:Isoenzymes; D008024:Ligands; D008081:Liposomes; D010703:Phorbol Esters; D011493:Protein Kinase C