Synthesis, molecular docking and antitumor activity of novel pyrrolizines with potential as EGFR-TK inhibitors.
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.
Pharmaceutical Chemistry Department, College of Pharmacy, Taif University, Taif 21974, Saudi Arabia; Medicinal Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt. Electronic address: abilalmoh1@yahoo.com.
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Belal
D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D000255:Adenosine Triphosphate; D066246:ErbB Receptors
Anticancer; EGFR tyrosine kinases; Pyrimidopyrrolizine; Pyrrolizine; TK inhibitors