title: Evaluation of (arene)Ru(II) complexes of curcumin as inhibitors of dipeptidyl peptidase IV.
abstract: Curcumin, the main component of Curcuma longa, shows an anti-hyperglycemic effect and improved insulin sensitivity. This action may be attributed at least in part to its anti-inflammatory properties and also to its possible interaction with dipeptidyl peptidase-4 (DPPIV), the enzyme that the conversion of glucagon-like peptide-1 (GLP-1), responsible for glucose tolerance into inactive GLP-1. In this work we evaluated the inhibitory activities of a series of different arene-Ru(II)-curcumin complexes on bovine kidney dipeptidyl peptidase-4 (DPPIV). We studied also the interaction of these inhibitors on the enzyme with fluorescence studies displaying the binding poses with molecular docking studies. Specifically organometallic ruthenium(II) complexes of general formula [(η(6)-arene)Ru(curcuminato)Cl], with arene being p-(i)PrC6H4Me (1), C6H6 (2), and C6Me6 (3), were evaluated for their inhibition activity toward the mammalian enzyme. Among them, 2 suppressed DPPIV activities more potently (Ki = 20.2(±0.8) μM) than 1, 3, or free curcumin, and all complexes showed an antioxidant activity as free curcumin. As shown from our docking simulations a putative binding site of the compound 2 was found on subdomains S1 and S2 of DPP-IV, where S1 hydrophobic pocket includes catalytic residues and is the primary determinant of substrate specificity for the enzyme. Collectively, our results demonstrate that the complexation of curcumin with ruthenium(II) could be a promising starting point for the development of curcumin-based DPPIV inhibitors.
authors: H. Buniatyan Institute of Biochemistry of Armenian NAS, Yerevan 0014, Armenia.
authors: A
authors: A
authors: Antonyan
authors: School of Pharmacy, Biology Section, University of Camerino, 62032 Camerino, Macerata, Italy.
authors: A
authors: A
authors: De
authors: School of Pharmacy, Biology Section, University of Camerino, 62032 Camerino, Macerata, Italy.
authors: L A
authors: LA
authors: Vitali
authors: School of Pharmacy, Chemistry Section, Via S. Agostino 1, 62032 Camerino, Italy.
authors: R
authors: R
authors: Pettinari
authors: School of Pharmacy, Chemistry Section, Via S. Agostino 1, 62032 Camerino, Italy.
authors: F
authors: F
authors: Marchetti
authors: School of Pharmacy, Chemistry Section, Via S. Agostino 1, 62032 Camerino, Italy.
authors: M R
authors: MR
authors: Gigliobianco
authors: School of Pharmacy, Chemistry Section, Via S. Agostino 1, 62032 Camerino, Italy.
authors: C
authors: C
authors: Pettinari
authors: Department of Pharmaceutical Sciences, University of Perugia, 06123 Perugia, Italy.
authors: E
authors: E
authors: Camaioni
authors: School of Pharmacy, Biology Section, University of Camerino, 62032 Camerino, Macerata, Italy. Electronic address: giulio.lupidi@unicam.it.
authors: G
authors: G
authors: Lupidi
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D002417:Cattle; D056831:Coordination Complexes / Q000737:chemistry*; D003474:Curcumin / Q000031:analogs & derivatives* / Q000737:chemistry*; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry*; D004353:Drug Evaluation, Preclinical; D016166:Free Radical Scavengers / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D012428:Ruthenium / Q000737:chemistry*
chemical_list: D056831:Coordination Complexes; D054873:Dipeptidyl-Peptidase IV Inhibitors; D016166:Free Radical Scavengers; D012428:Ruthenium; D018819:Dipeptidyl Peptidase 4; D003474:Curcumin
keywords: AutoDock; Curcumin; Dipeptidyl peptidase-4 (DPPIV); Docking; Ruthenium complexes