title: A novel 2,3-diphenyl-4H-pyrido[1,2-a]pyrimidin-4-one derivative inhibits endothelial cell dysfunction and smooth muscle cell proliferation/activation.
abstract: Hyper-proliferation and migration of vascular smooth muscle cells and endothelial cell dysfunction are central events in the development of neo-intimal lesions. Pursuing our interest in the synthesis of bioisosters of flavonoids, we studied in depth a novel synthetic 2,3-diphenyl-4H-pyrido[1,2-a]pyrimidin-4-one derivative, examining its effects in vitro on induced-cell proliferation and activation in human aortic smooth muscle cells (HAoSMCs) and in human umbilical vein endothelial cells (HUVECs). Compared with two well known flavonoids, apigenin and quercetin, the novel compound, 2-(3,4-dimethoxyphenyl)-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one, 3, was not toxic for HUVECs, even at high concentrations and for long incubation times, while the two flavonoids were not tolerated, even at concentrations as low as 10 μmol/L. Compound 3 inhibited selectively, and in a concentration-dependent manner, the proliferation of HAoSMCs but not that of HUVECs. In HUVECs, it inhibited the cytokine-induced vascular cell adhesion molecule-1 expression, but not the cyclooxygenase-2 (COX-2) expression. Instead, in HAoSMC, it inhibited the induction of COX-2 expression and the relative release of prostaglandin E2. In addition, it inhibited the transcription of the matrix metalloproteinase-9 and its activity. Thanks to its multiple and tissue-specific function, 2-(3,4-dimethoxyphenyl)-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one might replace or assist the action of current drugs eluted by coronary stents, in order to promote a functional repair of damaged wall.
authors.affiliation: CNR, Institute of Clinical Physiology, Via G. Moruzzi, 1, 56124 Pisa, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Del Turco
authors.affiliation: Department of Pharmacy, University of Pisa, Via Bonanno, 6, 56126 Pisa, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Sartini
authors.affiliation: CNR, Institute of Clinical Physiology, Via G. Moruzzi, 1, 56124 Pisa, Italy.
authors.forename: Cassandra
authors.initials: C
authors.lastname: Sentieri
authors.affiliation: CNR, Institute of Clinical Physiology, Via G. Moruzzi, 1, 56124 Pisa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Saponaro
authors.affiliation: CNR, Institute of Clinical Physiology, Via G. Moruzzi, 1, 56124 Pisa, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Navarra
authors.affiliation: Department of Pharmacy, University of Pisa, Via Bonanno, 6, 56126 Pisa, Italy.
authors.forename: Bianca
authors.initials: B
authors.lastname: Dario
authors.affiliation: Department of Pharmacy, University of Pisa, Via Bonanno, 6, 56126 Pisa, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Da Settimo
authors.affiliation: Department of Pharmacy, University of Pisa, Via Bonanno, 6, 56126 Pisa, Italy. Electronic address: concettina.lamotta@farm.unipi.it.
authors.forename: Concettina
authors.initials: C
authors.lastname: La Motta
authors.affiliation: CNR, Institute of Clinical Physiology, Via G. Moruzzi, 1, 56124 Pisa, Italy. Electronic address: lapina@ifc.cnr.it.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Basta
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D015394:Molecular Structure; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
chemical_list: C000593050:2-(3,4-dimethoxyphenyl)-3-phenyl-4H-pyrido(1,2-a)pyrimidin-4-one; D004791:Enzyme Inhibitors; D011725:Pyridines; D011744:Pyrimidinones; D019010:Vascular Cell Adhesion Molecule-1; D020780:Matrix Metalloproteinase 9
keywords: 2,3-Diphenyl-4H-pyrido[1,2-a]pyrimidin-4-ones; 2-(3,4-Dimethoxyphenyl)-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one; COX-2; Cell dysfunction; Cell proliferation; ECGF; HAoSMCs; HUVECs; Human aortic smooth muscle cells; Human umbilical vein endothelial cells; MMP-9; PDGF-BB; PGE(2); PGI(2); PMA; TNF-α; VCAM-1; cyclooxygenase-2; endothelial cell growth factor; human aortic smooth muscle cells; human umbilical vein endothelial cells; matrix metalloproteinase-9; phorbol 12-myristate 13-acetate; platelet derived growth factor-BB; prostacyclin; prostaglandin E(2); tumor necrosis factor-α; vascular cell adhesion molecule-1