Breast cancer is the second leading cause of cancer deaths in women today and is the most common cancer among women, excluding nonmelanoma skin cancers.1) Despite the progress achieved in anticancer therapy about 1.3 million women will be diagnosed with breast cancer annually worldwide and about 465000 will die from the disease.1) Accordingly, novel therapeutic strategies to improve prognosis are urgently needed.It is increasingly apparent that a number of protein tyrosine kinases, specifically epidermal growth factor receptor (EGFR) tyrosine kinase and/or its family members play a critical role in the development and progression of many solid tumors, including breast cancer.2,3) Over-expression of EGFR has been observed in about 70% of breast cancer 4) and is associated with later stages of carcinogenesis 5,6) and is implicated in the development of drug resistance with poor prognosis.7-9) Therefore inhibitors of EGFR kinase activity have emerged as promising new approach to cancer therapy.During the last decade azolidinones heterocycles, particularly imidazolidinones, thiazolidinones and pyrrolidinone have gained special attention as potential lead compounds for novel anticancer agents.10) The antineoplastic properties of azolidinones and related heterocycles are most probably caused by their affinity to different anticancer biotargets, such as extracellular signal-regulated kinases (ERK kinases), 11,12) JNK-stimulating phosphatase-1 (JSP-1) 1, 13) tumor necrosis factor-alpha (TNF-a), 14,15) antiapoptic complex Bcl-X L -BH3 2, 16) integrin a v b 3 receptor 3, 17) etc. (Fig. 1). Recent reports showed that imidazolidinones, and thiazolidinones were found to inhibit the kinase activity of EGFR. Where, some 1-phenethyl-5-(E)-benzylidine hydantoins 4 inhibited EGFR autophosphorylation and polyglutamic acid/ tyrosine (polyGAT) phosphorylation. 18,19) Moreover, a series of hydrazono thiazolidin-4-one 5 that own high antineoplastic activity against breast cancer cells MCF-7 and were potent inhibitors of EGFR autophosphorylation has been repoted. 20) Furthermore, dianilinophthalimide 6 that can bind competitively with the ATP to EGFR showed good selectivity between different tyrosine kinases.21) Therefore, azolidinones are considered good scaffolds for future design of tyrosine kinase inhibitors. In addition, benzamides and bezamidines were synthesized as mimics of the classical EGFR inhibitors 4-anilino-quinazolines.22) Also, we have recently reported preliminary results on antiproliferative action of 2,4Ј-bis-heterocyclic diphenylamine 7 against MCF-7 cell line, that might be mediated through the inhibition EGFR kinase activity.
23)Promoted by these observations and in continuation to the previous work, 23) we designed and synthesized hybrid molecules of diphenylamine-2,4Ј-dicarboxamide (as dibenzamide template) and different azolidinones or related heterocyclic rings 11, 13-17 aiming to obtain highly active antitumor agents, with probable EGFR tyrosine kinase inhibitory activity. The new hybrids were inspired by co...