Synthesis and biological evaluation of new coumarin derivatives as cytotoxic agents

Abstract

New coumarin derivatives 9a–f, 10a–e, and 11a–f were synthesized and evaluated for their cytotoxic activity against a human breast cancer cell line (MCF‐7). All compounds exhibited good activity in the nanomolar range, using doxorubicin and erlotinib as positive controls. The most active compound 9d with IC50 of 21 nM was tested against the HCT‐116, HepG‐2, A549, and SGC‐7901 cell lines, with IC50 values of 0.021, 0.170, 0.028, and 0.11 µM, respectively. Compound 9d was further investigated for its ability to suppress the expression of epidermal growth factor receptor (EGFR). Compound 9d decreased the concentration of EGFR by 87%, using erlotinib as a positive control. A docking study revealed similar or higher scores than for erlotinib and similar binding poses providing interactions with the hinge region of the tyrosine kinase (TK). Besides the effect on expression, this in silico investigation predicts the possibility of direct binding between the new coumarin derivatives and the EGFR TK. Moreover, computational calculation for ADME properties for the most active compounds 9d, 9e, 10c, and 11c revealed the expected high gastrointestinal tract absorption, moderate water solubility with no central nervous system toxicity, and druglikeness.

Molecular docking and molecular dynamics approach to identify EGFR and HER2 receptors inhibitory effect of compounds in Zanthoxylum simulans Hance

“…Erlotinib (IC 50 = 2 n m ) and icotinib (IC 50 = 5 n m ) are potent and selective EGFR inhibitors approved to treat non‐small cell lung cancer (NSCLC) 32–34 . In addition, erlotinib has been used as a positive control in several studies of EGFR inhibition 35–37 . Besides, Almalki Faisal et al.…”

“…[32][33][34] In addition, erlotinib has been used as a positive control in several studies of EGFR inhibition. [35][36][37] Besides, Almalki Faisal et al found that icotinib exhibited a binding energy of −8.42 kcal/mol compared with −7.26 kcal/mol for erlotinib, predicting that high binding affinity corresponds to the strong inhibitory effect on EGFR. 17 Also in this study, the authors demonstrated that both icotinib and erlotinib have similar hydrophobic interactions with hydrophobic moieties in EGFR, a finding that is consistent with our study.…”

Synthesis of Coumarin‐Thiazolidine‐2,4‐dione‐Pyrazole Hybrids as Epidermal Growth Factor Receptor (EGFR)‐Targeted Agents

“…Some of the compounds of coumarine and pyrazole were acting by inhibiting epidermal growth factor receptor [6b,33–35] . Accordingly, the five potent compounds 5 d , 5 e , 5 i , 5 j and 5 o were screened to know binding affinity towards epidermal growth factor receptor (EGFR) and the results were presented as table S1, in ESI.…”