title: Modulating the cyclic guanosine monophosphate substrate selectivity of the phosphodiesterase 3 inhibitors by pyridine, pyrido[2,3-d]pyrimidine derivatives and their effects upon the growth of HT-29 cancer cell line.
abstract: Analogues with the scaffolds of 3-cyano-4-alkoxyphenyl-6-bromoaryl-2-pyridone and 2-amino-3-cyano-4-alkoxyphenyl-6-bromoarylpyridine were synthesized. Cyclization of the 2-amino derivatives with formic acid and formamide gave the corresponding pyrido[2,3-d]pyrimidin-4(3H)-one and the pyrido[2,3-d]-pyrimidin-4-amine derivatives, respectively. Active phosphodiesterase 3 (PDE3) inhibitors were identified from each of the four aforementioned scaffolds. This is the first report that pyrido[2,3-d]pyrimidin-4(3H)-one and pyrido[2,3-d]pyrimidin-4-amine derivatives can inhibit PDE3. The analogues with the pyridone and pyrido[2,3-d]pyrimidin-4(3H)-one scaffolds inhibited both cAMP and cyclic guanosine monophosphate (cGMP) hydrolysis by PDE3, while the amine containing scaffolds were more selective for cGMP hydrolysis. This observation may set the base for substrate-selective pharmacological modulation of this important class of drug targets and with less side effects, particularly tachcardia. The dual inhibitors of PDE3 were more potent inhibitor towards the growth of HT-29 cancer cell lines.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Egypt. ashraf.abadi@guc.edu.eg
authors.forename: Ashraf Hassan
authors.initials: AH
authors.lastname: Abadi
authors.forename: Marwa Saeed
authors.initials: MS
authors.lastname: Hany
authors.forename: Shimaa Awadain
authors.initials: SA
authors.lastname: Elsharif
authors.forename: Amal Abdel Haleem
authors.initials: AA
authors.lastname: Eissa
authors.forename: Bernard Dewayne
authors.initials: BD
authors.lastname: Gary
authors.forename: Heather Nicole
authors.initials: HN
authors.lastname: Tinsley
authors.forename: Gary Anthony
authors.initials: GA
authors.lastname: Piazza
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D049109:Cell Proliferation / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000737:chemistry* / Q000378:metabolism; D003500:Cyclization; D019073:HT29 Cells; D006801:Humans; D006868:Hydrolysis; D062105:Molecular Docking Simulation; D058987:Phosphodiesterase 3 Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D058987:Phosphodiesterase 3 Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D006152:Cyclic GMP; C030986:pyrimidine; C023666:pyridine
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