Synthesis, cytotoxicity evaluation and molecular docking studies on 2 ',4 '-dihydroxy-6 '-methoxy-3 ',5 '-dimethylchalcone derivatives

2',4'-Dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC, 1) was isolated from seeds of Syzygium nervosum A.Cunn. ex DC. exhibiting intriguing biological activities. Herein, thirty three DMC derivatives including 4'-O-monosubstituted-DMC (2), 7-O-acylated-4-hydroxycoumarin derivatives (3), stilbene-coumarin derivatives (4), 2',4'-disubstituted-DMC (5), and flavanone derivatives (6), were synthesised through acylation, alkylations, and sulfonylation. These semi-synthetic DMC derivatives were evaluated for in vitro cytotoxicity against six carcinoma cell lines. It was found that most derivatives exhibited higher cytotoxicity than DMC. In particular, 4'-O-caproylated-DMC (2b) and 4'-O-methylated-DMC (2g) displayed the strongest cytotoxicity against SH-SY5Y with IC50 values of 5.20 and 7.52 mu M, respectively. Additionally, 4'-O-benzylated-DMC (2h) demonstrated the strongest cytotoxicity against A-549 and FaDu with IC50 values of 9.99 and 13.98 mu M, respectively. Our structure-activity relationship (SAR) highlights the importance of 2'-OH and the derivatisation pattern of 4'-OH. Furthermore, molecular docking simulation studies shed further light on how these bioactive compounds interact with cyclin-dependent kinase 2 (CDK2).