Design, Synthesis and Biological Evaluation of Heterocyclic Compounds As Potential Targeted Anticancer Agents

Abstract

Cancer is a fierce fighter, even after a long ongoing war; it is still fighting back through the emergence of drug resistances. EGFR (Epidermal Growth Factor Receptor) is a known key player in the development of many cancers, namely Non-small-cell Lung Cancer (NSCLC), Colorectal and breast cancer. Targeting EGFR with small molecules is a well-established therapeutic approach since the approval of Gefitinib in 2002. Among the various resistance mechanisms to EGFR inhibitors, our current study focuses on HER2 (Human Epidermal growth factor Receptor 2) amplification. Dual EGFR/HER2 targeting is expected to overcome EGFR inhibitors resistance by being able to simultaneously block the two counterparts of the HER family, thus blocking their downstream signaling pathway. Building on the classical kinase inhibitors design, and guided by molecular modeling, we designed a series of novel thieno[2,3-d]pyrimidine-based compounds with the aim of achieving dual EGFR/HER2 inhibition. The designed compounds were synthesized, purified and structurally confirmed by different analytical and spectral techniques. The study involved the synthesis of the following unavailable reported intermediates: (1) 2-chloro-1-((3-fluorobenzyl)oxy)-4-nitrobenzene (Ia) (2) 2-((2-chloro-4-nitrophenoxy)methyl)pyridine (Id) (3) 3-chloro-4-((3-fluorobenzyl)oxy)aniline (IIa) (4) 3-chloro-4-((3-chlorobenzyl)oxy)aniline (IIb) (5) 3-chloro-4-(pyridin-2-ylmethoxy)aniline (IId) (6) 2-chloro-4-nitro-1-(3-(trifluoromethyl)phenoxy)benzene (IIIa) (7) 3-chloro-4-(3-(trifluoromethyl)phenoxy)aniline (IVa) (8) 3-chloro-4-(m-tolyloxy)aniline (IVb) (9) 1-benzyl-5-nitro-1H-indazole (V) (10) 1-benzyl-1H-indazol-5-amine (VI) (11) (E)-N,N-dimethyl-2-(4-nitrophenyl)ethenamine (IX) (12) Ethyl 2-amino-5-(4-nitrophenyl)thiophene-3-carboxylate (X)

In addition to the following new intermediates: