title: Synthesis and evaluation of c-Src kinase inhibitory activity of pyridin-2(1H)-one derivatives.
abstract: Src kinase, a prototype member of the Src family of kinases (SFKs), is over-expressed in various human tumors, and has become a target for anticancer drug design. In this perspective, a series of eighteen 2-pyridone derivatives were synthesized and evaluated for their c-Src kinase inhibitory activity. Among them, eight compounds exhibited c-Src kinase inhibitory activity with IC50 value of less than 25μM. Compound 1-[2-(dimethylamino)ethyl]-5-(2-hydroxy-4-methoxybenzoyl)pyridin-2(1H)-one (36) exhibited the highest c-Src kinase inhibition with an IC50 value of 12.5μM. Furthermore, the kinase inhibitory activity of compound 36 was studied against EGFR, MAPK and PDK, however no significant activity was observed at the highest tested concentration (300μM). These results provide insights for further optimization of this scaffold for designing the next generation of 2-pyridone derivatives as candidate Src kinase inhibitors.
authors.affiliation: Department of Chemistry, University of Delhi, Delhi 110007, India.
authors.forename: Karam
authors.initials: K
authors.lastname: Chand
authors.affiliation: Department of Chemistry, University of Delhi, Delhi 110007, India.
authors.forename: Suchita
authors.initials: S
authors.lastname: Prasad
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island, Kingston, RI 02881, USA; School of Pharmacy, Chapman University, One University Drive, Orange, CA 92866, USA.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Tiwari
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island, Kingston, RI 02881, USA; School of Pharmacy, Chapman University, One University Drive, Orange, CA 92866, USA.
authors.forename: Amir N
authors.initials: AN
authors.lastname: Shirazi
authors.affiliation: Department of Chemistry, University of Delhi, Delhi 110007, India; Department of Chemistry, Deenbandhu Chhotu Ram University of Science & Technology, Murthal 131039, Haryana, India.
authors.forename: Sumit
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island, Kingston, RI 02881, USA; School of Pharmacy, Chapman University, One University Drive, Orange, CA 92866, USA. Electronic address: kparang@uri.edu.
authors.forename: Keykavous
authors.initials: K
authors.lastname: Parang
authors.affiliation: Department of Chemistry, University of Delhi, Delhi 110007, India. Electronic address: sk.sharma90@gmail.com.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Sharma
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D000081247:CSK Tyrosine-Protein Kinase; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D066246:ErbB Receptors; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D017346:Protein Serine-Threonine Kinases; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: Chromone; Pyridin-2(1H)-one; Synthesis; c-Src kinase inhibition