Integrated in silico and in vitro study of microwave-synthesized prenylated rutin derivatives for anticancer activity

An effective microwave-assisted technique for the synthesis of three prenylated flavonoid derivatives originating from rutin, 3,7,3′,4′-tetramethoxy-8-prenylflavanol ( 2 ), and 8-prenylquercetin ( 3 ). The synthesis includes essential stages such as rutin hydrolysis, selective O -methylation, O-prenylation, and Claisen rearrangement facilitated by microwave irradiation. The final product yields were around 23 %, 8 %, and 25 %, respectively. The utilization of microwave help significantly enhanced the efficiency and selectivity of the prenylation process. The structures of compounds have confirmed using 1 H NMR, 13 C NMR, and mass spectrometry methods. Biological investigations indicated that all three compounds exhibited moderate to significant cytotoxic effects on HeLa, HCC1954, and LC cancer cell lines, as determined by CCK-8 assays. Compounds ( 1 ) and ( 3 ) had notable efficacy against HCC1954 cells, with IC50 values of 4.76 μM and 7.58 μM, respectively. Moreover, compound ( 1 ) exhibited significant antioxidant activity in the ABTS• + experiment (IC 50 = 9.38 μM), comparable to the standard antioxidant Trolox (IC 50 = 6.16 μM). In silico docking, compound (1), specifically the optimal docking pose 276, has interacted with the 1T8I enzyme, yielding free Gibbs energy and inhibition constant values of −6.6 Kcal.mol −1 and 14.51 μM, respectively. Molecular dynamics simulations of the complex comprising posture 276 and 1T8I, conducted using Desmond-Schrodinger software on Ubuntu, have revealed a stable complex from 0 to 40 ns and from 60 to 100 ns of trajectory, with RMSD variations for pose 276 and enzyme 1T8I ranging from 1 to 1.5 Å and 4 to 6 Å, respectively. The remaining amino acids on 1T8I that interacted most frequently with position 276 are Thr 718 and His 632, which established hydrogen bonds with pose 276 through water bridges. The validations of the docking model for pose 276 to 1T8I have been corroborated by the RMSD curve values of posture 276 aligned to 1T8I, which range from 1 to 1.5 Å. • The effective microwave-assisted technique for the synthesis of three prenylated flavonoid derivatives originating from rutin: ( 1 ), ( 2 ), and ( 3 ). • The final product yields were around 23, 8, and 25 %, respectively. • Cytotoxic on HeLa, HCC1954, and LC cancer cell lines, via CCK-8 assays, ( 1 ) and ( 3 ) inhibited HCC1954 cells: IC 50 - 4.76 μM, 7.58 μM, respectively. • ( 1 ) exhibited significant antioxidant activity in the ABTS• + , IC 50 : 9.38 μM, comparable to the standard antioxidant Trolox, IC 50 : 6.16 μM. • MD: pose 276 and 1T8I: the stable complex: 0 to 40 ns, 60 to 100 ns, RMSD: pose 276: 1 to 1.5 Å, 1T8I: 4 to 6 Å, Thr718 and His 632: the most interactions.