Synthesis and evaluation of c-Src kinase inhibitory activity of pyridin-2(1H)-one derivatives

Karam Chand; Suchita Prasad; Rakesh K Tiwari; Amir N Shirazi; Sumit Kumar; Keykavous Parang; Sunil K Sharma

doi:10.1016/j.bioorg.2014.02.001

Synthesis and evaluation of c-Src kinase inhibitory activity of pyridin-2(1H)-one derivatives

Bioorg Chem. 2014 Apr:53:75-82. doi: 10.1016/j.bioorg.2014.02.001. Epub 2014 Feb 17.

Authors

Karam Chand¹, Suchita Prasad¹, Rakesh K Tiwari², Amir N Shirazi², Sumit Kumar³, Keykavous Parang⁴, Sunil K Sharma⁵

Affiliations

¹ Department of Chemistry, University of Delhi, Delhi 110007, India.
² 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.
³ Department of Chemistry, University of Delhi, Delhi 110007, India; Department of Chemistry, Deenbandhu Chhotu Ram University of Science & Technology, Murthal 131039, Haryana, India.
⁴ 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.
⁵ Department of Chemistry, University of Delhi, Delhi 110007, India. Electronic address: sk.sharma90@gmail.com.

PMID: 24632506
DOI: 10.1016/j.bioorg.2014.02.001

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.

Keywords: Chromone; Pyridin-2(1H)-one; Synthesis; c-Src kinase inhibition.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Antineoplastic Agents / toxicity
CSK Tyrosine-Protein Kinase
Cell Line, Tumor
Cell Survival / drug effects
Enzyme Activation / drug effects
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / metabolism
Humans
MCF-7 Cells
Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
Mitogen-Activated Protein Kinase Kinases / metabolism
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors
Protein Serine-Threonine Kinases / metabolism
Pyridones / chemical synthesis
Pyridones / chemistry*
Pyridones / pharmacology*
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
src-Family Kinases / antagonists & inhibitors*
src-Family Kinases / metabolism

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyridones
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
ErbB Receptors
CSK Tyrosine-Protein Kinase
src-Family Kinases
CSK protein, human
Protein Serine-Threonine Kinases
Mitogen-Activated Protein Kinase Kinases

Grants and funding

8 P20 GM103430-12/GM/NIGMS NIH HHS/United States