Molecular Design and Synthesis of Certain Heterocycles as Targeted Anticancer Agents

Abstract

According to American Cancer Society (ACS) statistics, cancer is the third most lethal disease following cardiovascular diseases, infectious diseases, and parasites. Cancer treatment tend to be one of the most important fields of scientific research. Targeted therapy is a cancer treatment that uses drugs to target specific genes and proteins that are involved in the growth and survival of cancer cells; tyrosine kinase inhibitors (TKIs) are a type of targeted therapy. The formation of new blood vessels (angiogenesis) is one of the hallmarks well known in the carcinogenesis cycle. Vascular endothelial receptor-2 growth factor (VEGFR-2) plays a significant role in angiogenesis of cancer. Angiogenesis is greatly inhibited by targeting VEGFR which leads to tumor cell death. MYT1 (Membrane-associated tyrosine and threonine-specific cdc2-inhibitory kinase) is one of WEE kinase family that regulate and control cell cycle through phosphorylation of Cdk1/Cyclin B complex at G2/M transition which essential to entry into mitotic phase. Consequently, inhibition of MYT1 is promising target for synergistic action with convential cancer therapy to target cancer cell over non-cancerous cells. In this study, quinazoline and quinoline derivatives were developed and synthesized as targeted inhibitors of VEGFR-2 and MYT1 kinases. The design centered on the scaffold hopping, redesign approach and analysis of previous SAR studies to approved lead compounds and in clinical studies ones; Synthesis of the designed compounds was then achieved, and various spectral and microanalytical data validated their structures. This study involved the synthesis of the following commercially unavailable reported intermediates: 1) 1-(4-Nitrophenyl)-3-phenylurea (Ia) 2) 1-(3-Fluorophenyl)-3-(4-nitrophenyl)urea (Ib) 3) 1-(4-Fluorophenyl)-3-(4-nitrophenyl)urea (Ic) 4) 1-(3-Methoxyphenyl)-3-(4-nitrophenyl)urea (Id) 5) 1-(4-Methoxyphenyl)-3-(4-nitrophenyl)urea (Ie) 6) 1-(4-Chlorophenyl)-3-(4-nitrophenyl)urea (If) 7) 1-(4-Nitrophenyl)-3-(3-(trifluoromethyl)phenyl)urea (Ig) 8) 1-(3,4-Dichlorophenyl)-3-(4-nitrophenyl)urea (Ih) 9) 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-nitrophenyl)urea (Ii) 10) 1-(4-Aminophenyl)-3-phenylurea (IIa) 11) 1-(4-Aminophenyl)-3-(4-fluorophenyl)urea (IIb) 12) 1-(4-Aminophenyl)-3-(4-fluorophenyl)urea (IIc)