Synthesis of phthalazine-based derivatives as selective anti-breast cancer agents through EGFR-mediated apoptosis: in vitro and in silico studies
Sara M. Emam, Samir M. El Rayes, Ibrahim A. I. Ali, Hamdy A. M. Soliman, Mohamed S. Nafie
Abstract
Abstract The parent 2-(4-benzyl-1-oxophthalazin-2(1 H )-yl)-acetohydrazide (4) has twenty-nine compounds. The starting material for their corresponding mono, dipeptides and reactions with active methylene compounds were produced by chemoselective N -alkylation of 4-Benzyl-2 H -phthalazin-1-one (2) with ethyl chloroacetate to afford (4-benzyl-1-oxo-1 H -phthalazin-2-yl) methyl acetate (3) . The ester 3 was hydrazinolyzed to give hydrazide 4 , then azide 5 coupled with amino acid ester hydrochloride and/or amines to produce several monopeptides, then the methyl (2-(4-benzyl-1-oxophthalazin-2(1 H )-yl) acetyl) glycinate (7a) was hydrazinolyzed to produce corresponding hydrazide 2-(4-benzyl-1-oxophthalazin-2(1 H )-yl)- N -(2-hydrazineyl-2-oxo ethyl) acetamide (8a) . The hydrazide 8a under azide coupling method was coupled with amino acid ester hydrochloride and/or amines to produce several dipeptides, and the hydrazide 8a was also condensed and/or cyclized with several carbonyl compounds. The cytotoxicity of the synthesized compounds was tested using MTT assay, as well as apoptosis-induction through EGFR inhibition. Compounds 11d , 12c and 12d exhibited potent cytotoxic activities with IC 50 values of 0.92, 1.89 and 0.57 μM against MDA-MB-231 cells compared to Erlotinib (IC 50 = 1.02 μM). Interestingly compound 12d exhibited promising potent EGFR inhibition with an IC 50 value 21.4 nM compared to Erlotinib (IC 50 = 80 nM). For apoptosis, compound 12d induced apoptosis in MDA-MB-231 cells by 64.4-fold (42.5% compared to 0.66 for the control); hence, this compound may serve as a potential target-oriented anti-breast cancer agent. These results agreed with the molecular docking studies that highlighted the binding disposition of compound 12d towards EGFR protein. Hence, compound 12d may serve as a potential and selective anti-breast cancer agent.