Thiazolyl N-benzyl-substituted acetamide derivatives: synthesis, Src kinase inhibitory and anticancer activities

Asal Fallah-Tafti; Alireza Foroumadi; Rakesh Tiwari; Amir Nasrolahi Shirazi; David G Hangauer; Yahao Bu; Tahmineh Akbarzadeh; Keykavous Parang; Abbas Shafiee

doi:10.1016/j.ejmech.2011.07.050

Thiazolyl N-benzyl-substituted acetamide derivatives: synthesis, Src kinase inhibitory and anticancer activities

Eur J Med Chem. 2011 Oct;46(10):4853-8. doi: 10.1016/j.ejmech.2011.07.050. Epub 2011 Aug 4.

Authors

Asal Fallah-Tafti¹, Alireza Foroumadi, Rakesh Tiwari, Amir Nasrolahi Shirazi, David G Hangauer, Yahao Bu, Tahmineh Akbarzadeh, Keykavous Parang, Abbas Shafiee

Affiliation

¹ Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14176, Iran.

PMID: 21852023
DOI: 10.1016/j.ejmech.2011.07.050

Abstract

KX2-391 (KX-01/Kinex Pharmaceuticals), N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide, is a highly selective Src substrate binding site inhibitor. To understand better the role of pyridine ring and N-benzylsubstitution in KX2-391 and establish the structure-activity relationship, a number of N-benzyl substituted (((2-morpholinoethoxy)phenyl)thiazol-4-yl)acetamide derivatives containing thiazole instead of pyridine were synthesized and evaluated for Src kinase inhibitory activities. The unsubstituted N-benzyl derivative (8a) showed the inhibition of c-Src kinase with GI(50) values of 1.34 μM and 2.30 μM in NIH3T3/c-Src527F and SYF/c-Src527F cells, respectively. All the synthesized compounds were evaluated for inhibition of cell proliferation of human colon carcinoma (HT-29), breast carcinoma (BT-20), and leukemia (CCRF-CEM) cells. 4-Fluorobenzylthiazolyl derivative 8b exhibited 64-71% inhibition in the cell proliferation of BT-20 and CCRF cells at concentration of 50 μM.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Acetamides / chemical synthesis
Acetamides / chemistry*
Acetamides / pharmacology*
Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Breast Neoplasms / drug therapy
Cell Line, Tumor
Cell Proliferation / drug effects
Colonic Neoplasms / drug therapy
Female
Humans
Inhibitory Concentration 50
Leukemia / drug therapy
Mice
Morpholines
NIH 3T3 Cells
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*
Pyridines / chemical synthesis
Pyridines / chemistry*
Pyridines / pharmacology*
Structure-Activity Relationship
Thiazoles / chemical synthesis
Thiazoles / chemistry
Thiazoles / pharmacology
src-Family Kinases / antagonists & inhibitors*
src-Family Kinases / metabolism

Substances

Acetamides
Antineoplastic Agents
Morpholines
Protein Kinase Inhibitors
Pyridines
Thiazoles
tirbanibulin
acetamide
src-Family Kinases