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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)4853-4858
Number of pages6
JournalEuropean Journal of Medicinal Chemistry
Volume46
Issue number10
DOIs
StatePublished - Oct 2011
Externally publishedYes

Keywords

  • Anticancer
  • Cell proliferation
  • Inhibitor
  • KX-2
  • Src kinase
  • Thiazole

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

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