title: Synthesis and biological evaluation of novel pyridine derivatives as potential anticancer agents and phosphodiesterase-3 inhibitors.
abstract: Phosphodiesterases (PDEs) have been studied in a variety of tumours; data have suggested that the levels of PDE activities are elevated and, therefore, the ratios of cGMP to cAMP are affected. In addition, PDE inhibitors are potential targets for tumour cell growth inhibition and induction of apoptosis. Nonselective PDE inhibitors, such as theophylline or aminophylline, are known regulators of growth in a variety of carcinoma cell lines, suggesting a potential role for PDE inhibitors as anticancer drugs. In the current study, we reported the synthesis of novel derivatives of 6-aryl-4-imidazolyl-2-imino-1,2-dihydropyridine-3-carbonitriles (Ia,b,c) and their 2-oxo isosteres (IIa,b,c,d). All the compounds were evaluated for their PDE3A inhibitory effects, as well as their cytotoxic effects on MCF-7 and HeLa cell lines. Moreover, structure-activity relationships were studied. 4-(1-benzyl-2-ethylthio-5-imidazolyl)-6-(4-bromophenyl)-2-imino-1,2-dihydropyridine-3-carbonitrile (Ib) exhibited the strongest PDE3A inhibitory effects with an IC50 of 3.76±1.03nM. Compound Ib also showed the strongest cytotoxic effects on both the HeLa and MCF-7 cells with an IC50 of 34.3±2.6μM and 50.18±1.11μM, respectively. There was a direct correlation between PDE3 inhibition and anticancer activity for the synthesised compounds. The data reported here support our view that PDEs represent promising cellular targets for antitumor treatment.
authors.affiliation: Student Research Committee, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
authors.forename: Atieh Sadat
authors.initials: AS
authors.lastname: Davari
authors.affiliation: Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
authors.forename: Khalil
authors.initials: K
authors.lastname: Abnous
authors.affiliation: Pharmaceutical Research Center, Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
authors.forename: Soghra
authors.initials: S
authors.lastname: Mehri
authors.affiliation: Biotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
authors.forename: Morteza
authors.initials: M
authors.lastname: Ghandadi
authors.affiliation: Biotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address: hadizadehf@mums.ac.ir.
authors.forename: Farzin
authors.initials: F
authors.lastname: Hadizadeh
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D058987:Phosphodiesterase 3 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D058987:Phosphodiesterase 3 Inhibitors; D011725:Pyridines; D010727:Phosphoric Diester Hydrolases; C023666:pyridine
keywords: Anticancer; Inhibition; Phosphodiesterase; Synthesis