title: Synthesis of new pyridothienopyrimidinone derivatives as Pim-1 inhibitors.
abstract: Four series of pyridothienopyrimidin-4-one derivatives were designed and prepared to improve the pim-1 inhibitory activity of the previously reported thieno[2,3-b]pyridines. Significant improvement in the pim-1 inhibition and cytotoxic activity was achieved using structure rigidification strategy via ring closure. Six compounds (6c, 7a, 7c, 7d, 8b and 9) showed highly potent pim-1 inhibitory activity with IC50of 4.62, 1.18, 1.38, 1.97, 8.83 and 4.18 μM, respectively. Four other compounds (6b, 6d, 7b and 8a) showed moderate pim-1 inhibition. The most active compounds were tested for their cytotoxic activity on three cell lines [MCF7, HCT116 and PC3]. Compounds 7a [the 2-(2-chlorophenyl)-2,3-dihydro derivative] and 7d [the 2-(2-(trifluoromethyl)-phenyl)-2,3-dihydro derivative] displayed the most potent cytotoxic effect on the three cell lines tested consistent with their highest estimated pim-1 IC50values.
authors.affiliation: a Pharmaceutical Chemistry Department, Faculty of Pharmacy , The British University in Egypt , Cairo , Egypt.|b Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy , Cairo University , Cairo , Egypt.
authors.forename: Bassem H
authors.initials: BH
authors.lastname: Naguib
authors.affiliation: b Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy , Cairo University , Cairo , Egypt.
authors.forename: Hala B
authors.initials: HB
authors.lastname: El-Nassan
authors.affiliation: c Department of Pharmacology and Toxicology, Faculty of Pharmacy , Al-Azhar University , Cairo , Egypt.
authors.forename: Tamer M
authors.initials: TM
authors.lastname: Abdelghany
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D020128:Inhibitory Concentration 50; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors*; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D011744:Pyrimidinones; D051573:Proto-Oncogene Proteins c-pim-1
keywords: Pyridothienopyrimidine; cytotoxic activity; pim-1 inhibitors; pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4(3H)-one