Design, synthesis, and molecular docking of 1,4-naphthoquinone based glycoconjugates as chiral glycohybrids targeting lung cancer

Carbohydrate derivatives and 1,4-naphthoquinone analogues are crucial in many life-saving drugs, and their presence in numerous FDA-approved medications underscores their significance in drug design. In light of this, we have identified a mild and efficient copper-catalyzed click chemistry reaction conditions to synthesize two new series of 1,4-naphthoquinone based triazole-linked glycoconjugates as chiral glycohybrids, and evaluated their Anticancer activity against non-small cell lung adenocarcinoma (A549) cell lines. A significant number of glycohybrids showed Anticancer activity against A549 cells with IC₅₀ in the micromolar range. It was observed that these glycohybrids caused cell death in A549 cells through the induction of Apoptosis. Specifically, compounds 5c (IC₅₀ = 5.17 μM), from O-triazole-linked series; and 6d (IC₅₀ = 7.89 μM) from N-triazole-linked series were most effective Anticancer molecules. These two compounds were found to inhibit the cell growth of resistant lung Cancer cells H1922 (IC₅₀ = 7.97 μM for 5c and 6.94 μM for 6d) and H1975 (IC₅₀ = 9.74 μM for 5c and 9.59 μM for 6d) at sub-micromolar concentration. These active glycohybrids induced Apoptosis by inhibiting the expression of anti-apoptotic protein Bcl₂ and activating the expression of pro-apoptotic protein Bax leading to a significantly increased ratio of Bax/Bcl₂ which suggests cell death through Apoptosis. The detailed results obtained suggest that triazole-linked glycoconjugates synthesized by us using copper-catalyzed click chemistry reactions exhibit anti-cancer properties against lung Cancer cells by inducing apoptotic cell death in-vitro. Additionally, molecular docking studies of these glycohybrids against EGFR (PDB ID:1M17) protein (over-expressed in non-small A549 lung Cancer cells) revealed significant interactions between the protein and our synthesized glycohybrids (ligands) at the active site. Thus, the molecular docking studies with EGFR protein show that compound 5c, with a superior docking score of -6.78 kcal/mol, could be the most promising inhibitor of EGFR.

Anticancer activity; Apoptosis; Click chemistry; EGFR protein; Glycohybrids; Naphthoquinone.