作者
Nguyễn Đình Thành,Do Son Hai,Le Thi Huyen,Nguyễn Đình Thành,Nguyễn Thị Thu Hà,Do Tien Tung,Cao Thi Le,Hoàng Thi Kim Van,Vu Ngoc Toan
摘要
The polysubstituted 4H-pyrano[2,3-d]pyrimidines 6a-zj containing propargyl group on nitrogen atom 3 of ring have been synthesized by ring-closing reaction of corresponding 2-amino-3-cyano-4H-pyrans 4a-zj with acetic anhydride and trifluoroacetic acid as catalyst, followed by alkylation with propargyl bromide under ultrasound conditions. A series of 36 analogs of 4H-pyrano[2,3-d]pyrimidine 8a-zj bearing d-glucose moiety tethered 1,2,3-triazole derivatives, including eighteen new ones, were synthesized by click chemistry between these N-propargyl derivatives and peracetylated d-glucopyaranosyl azide, with using CuNPs@Montmorillonite as a catalyst under ultrasound condition in the presence of DIPEA in t-BuOH/H2O at 25°C for 20 min. These compounds exhibited potent anticancer activity against tested cancer cells, including MCF-7, HepG2, and HeLa. Amongst tested compounds, some compounds exhibited strong activity against tested cancer cell lines with IC50 < 4 μM, such as 8v,8x,8z,8zc,8zf and 8zg against MCF-7, 8s,8t,8w,8zh, and 8zi against HepG2, 8h,8j,8zf and 8zh against HeLa cancer cell lines. Compounds 8v,8z,8zc, and 8zf exhibited remarkable inhibitory activity against EGFR and HER2 tyrosine kinases in comparison with Lapatinib. The resulted docking studies showed that compound 8zc displayed binding mode like Erlotinib on EGFR enzyme and showed good binding energies. Induced fit docking, MM-GBSA calculation, and molecular dynamics simulations were carried out to elucidate the inhibitory potential of compound 8zc against tested enzyme 4HJO. Docking analysis showed that amongst the hydrophilic and hydrophobic interactions at the active site of EGFR enzyme, the hydrogen-bond bindings between acetate function and appropriate amino acid residues displayed the most important contribution in intensifying their potency against this enzyme.