Design and synthesis of new series 6, 7-disubstituted-7H-purine analogues induce G2/M cell cycle arrest and apoptosis in human breast cancer SKBR3 cells via selective EGFR/HER2 dual kinase inhibition
Abstract
A unique series of 6, 7-disubstituted 7H-purine analogues were designed with the goal of developing potential EGFR/HER2 dual tyrosine kinase inhibitors to treat human breast cancers. The compounds were rationally developed by replacing the central quinazoline core of lapatinib, an established drug that suppresses both EGFR and HER2, another essential member of this receptor family. Twelve compounds were synthesized by substituting hydrophilic '6-(3-chloro-4-[(substituted pyridin-3-yl) oxy]) anilino' group at 6th position and '(3E)-5-(dimethylamino) pent-3-en-2-ol' side chain at 7th position of purine scaffold which was thought to be considered critical for dual EGFR/HER2 inhibition. The chemical structures of the synthesized compounds were confirmed by 1H, 13C NMR, and HRMS analysis. All these compounds were evaluated for EGFR family tyrosine kinase (EGFR, HER2, HER3, and HER4) in-vitro inhibition. The results showed compound 8e as a potent dual EGFR/HER2 inhibitor with IC50 values of 0.021 ± 0.007 µM (EGFR) and 0.019 ± 0.009 µM (HER2), respectively, which were comparable to lapatinib (EGFR: 0.019 ± 0.007; HER2: 0.016 ± 0.003 µM), a positive control. EGFR/HER2 phosphorylation inhibition studies proved potential for 8e in dual kinase inhibition. In support of the dual inhibitory activity against both EGFR and HER2, compound 8e exhibited potent cytotoxic activity against BT-474 and SKBR3 cells, with IC50 values of 2.26 ± 0.37 µM (BT-474) and 2.17 ± 0.45 µM (SKBR3), which was comparable to the standard Lapatinib (EGFR: 2.63 ± 0.45 µM; HER2: 1.84 ± 0.39 µM). Additionally, compound 8e caused significant G2/M phase cell cycle arrest, resulting in a fivefold increase in cell number compared to control SKBR3 cells, and potentially induced apoptosis in 79% of these cells, which was comparable to that of lapatinib (83%). These new findings could provide an important basis for further developing compound 8e as a potent EGFR/HER2 dual kinase inhibitor.
Keywords:
EGFR, HER2, 6, 7-disubstituted 7H-purine, IC50, Breast cancer, lapatinibDOI
https://doi.org/10.25004/IJPSDR.2022.140407References
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