Design and Synthesis of Molecular Candidates for Kinase Inhibition as Potential Antiproliferative Agents

Abstract

Cancer is characterized by the rapid creation of abnormal cells that grow beyond their usual boundaries and can then metastasize to other organs. Cancer is one of the leading causes of death worldwide, with approximately 14 million new cases and 8.2 million cancer related deaths in 2012. The HER family plays important roles in normal physiology and in cancer because of their essential role for intracellular signaling and cell transformation. Among this family, two members are particularly involved in cancer development; EGFR and HER2. EGFR overexpression is notable in many types of human cancers and it is responsible for poor prognosis. In particular, overexpression of EGFR has been found in 40-80% of NSCLC cases. NSCLC accounts for approximately 85% of primary malignant lung tumors and it remains the leading cause of cancer-related death worldwide. Meanwhile, HER2 has been identified as a prognostic and predictive factor in breast cancer (18–25%).Therefore, the HER family represents an attractive class of rational targets for anticancer drug development. The current study aimed to design novel furo[2,3-d]pyrimidine derivatives targeting EGFR and HER2. The design focused on exploration of the previously revealed SAR studies and bioisosteric modifications of the lead compounds both in market and in clinical studies. Synthesis of the designed compounds was then accomplished & their structures were confirmed by various spectral and microanalytical data. This study involved the synthesis of the following unavailable reported intermediates: 1) 1-(benzyloxy)-4-nitrobenzene (Ia) 2) 1-fluoro-3-((4-nitrophenoxy)methyl)benzene (Ib) 3) 1-chloro-3-((4-nitrophenoxy)methyl)benzene (Ic) 4) 1-chloro-4-((4-nitrophenoxy)methyl)benzene (Ie) 5) 1-methyl-4-((4-nitrophenoxy)methyl)benzene (If) 6) 1,2-dichloro-4-((4-nitrophenoxy)methyl)benzene (Ig) 7) 2-chloro-1-((3-fluorobenzyl)oxy)-4-nitrobenzene (Ih) 8) 2-((2-chloro-4-nitrophenoxy)methyl)pyridine (Ii) 9) 4-(benzyloxy)aniline (IIa) 10) 4-((3-fluorobenzyl)oxy)aniline (IIb) 11) 4-((3-chlorobenzyl)oxy)aniline (IIc)