Synthesis, molecular docking and antitumor activity of novel pyrrolizines with potential as EGFR-TK inhibitors

• Design and synthesis of new pyrrolizines.
• Anticancer activity evaluation against MCF7, HEPG2 and HCT116.
• Docking studies into ATP binding site of EGFR-TK.
• Evaluating the new compounds as inhibitors for EGFR-TK.

A new series of pyrrolizine derivatives 4–8c were synthesized, their structures were confirmed by spectral and elemental analyses. Cytotoxic activity of these compounds was evaluated against breast (MCF7), colon (HCT116) and liver (HEPG2) cancer cell lines using sulphorhodamine-B (SRB) assay method. All the tested compounds showed highly potent activity against MCF7 cell line with IC50 range equal 8–194 nM/ml and compound 8c was the best active one (IC50 = 8.6 nM/ml). 8b was the best active compound on both HCT116 and HEPG-2 cancer cell lines; its IC50 is 26.5 and 12.3 nM/ml respectively. Docking studies into ATP binding site of EGFR tyrosine kinase were performed to predict their scores and mode of binding to amino acids, moreover, inhibitory activity of these compounds against EGFR-TKs was evaluated; their inhibitory percent ranged from 40.4 to 97.6, compound 8c and 8b showed inhibitory activity at 97.6% and 88.4% respectively.

8b, R = morpholin-4-yl IC50 = 12.3 nM/ml against IEPG2, 26.5 nM/ml against HCT116 and 88.4 EGFR-TK inhibitory percent.8c, R = thiomorpholin-4-yl IC50 = 8.6 nM/ml against MCF7, 44 nM/ml against HEPG2 and 97.6 EGFR-TK inhibitory percent.Figure optionsDownload as PowerPoint slide