Synthesis, Single Crystal X-Ray Structure, Hirshfeld Surface Analysis, DFT Computations, Docking Studies on Aurora Kinases and an Anticancer Property of 3-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-6-methoxy-4H-chromen-4-one

Abstract

The isoflavone compound 3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-methoxy-4H-chromen-4-one (6) was prepared and structurally characterized using NMR, mass spectrum and X-ray crystallography. Compound 6, C18H14O5, was crystallized in the monoclinic space group P21/n with the cell parameters; a = 7.1869(4) Å, b = 10.2764(6) Å, c = 19.6771(10) Å, β = 99.442(2)°, V = 1433.57(14) Å3, Z = 4. In the title compound, the chromenone ring system is slightly twisted from planarity and the dihedral angle formed between the plane of the chromenone ring and benzene ring is 47.75°. Several intermolecular hydrogen bonds make the crystal stabilized in the three-dimensional structure, which was confirmed by Hirshfeld surface analysis. Density functional theory (DFT) calculations at the B3LYP/6-311++G(d,p) level were carried out and the calculated geometric parameters were compared with the experimental results. A frontier molecular orbital calculation was performed to reveal that the energy values of highest occupied molecular orbital (HOMO) and lowest un-occupied molecular orbital (LUMO) were −5.8223 eV and −1.8447 eV, and the HOMO–LUMO energy gap was 3.9783 eV. A clonogenic long-term survival assay of compound 6 against HCT116 human colon cancer cells showed an anti-cancer ability, with GI50 value of 24.9 μM. Docking experiments within the active sites of aurora kinase A and B were carried out to explain the anti-cancer property of compound 6.

Single Crystal X-Ray Structure for the Disordered Two Independent Molecules of Novel Isoflavone: Synthesis, Hirshfeld Surface Analysis, Inhibition and Docking Studies on IKKβ of 3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6,7-dimethoxy-4H-chromen-4-one

“…NMR experiments were carried out on a Bruker Avance 400 spectrometer Q (Bruker, Karlsruhe, Germany). The detailed procedures and parameters for the NMR experiments followed to the methods reported previously [34]. Other general experimental methods were followed by the methods reported previously [35].…”

“…The title compound 5 was synthesized as shown in Scheme 1 by literature methods [34,44,45]. The final compound 5 was obtained by palladium-catalyzed Suzuki reaction between boronic acid (4) derivative and 3-iodoflavone (3) in three steps from the commercially available starting material.…”

“…3.1.1. Synthesis of (E)-3-(dimethylamino)-1-(2-hydroxy-4,5-dimethoxyphenyl)prop-2-en-1-one (2) The previously reported literature procedures were used, but starting with 2-hydroxy-4,5-dimethoxyacetophenone (1) [34,44]. 1 13 C NMR (400 MHz, DMSO-d6) δ 173.9 (C-4), 154.2 (C-7), 152.8 (C-2), 151.5 (C-9), 147.4 (C-6), 143.0 (C-4′), 142.8 (C-3′), 124.9 (C-1′), 122.4 (C-3), 121.5 (C-6′), 117.3 (C-2′), 117.0 (C-10), 116.4 (C-5′), 104.4 (C-5), 100.1 (C-8), 63.90 (C-3′), 63.86 (C-4′), 56.1 (7-OCH3), 55.7 (6-OCH3).…”

“…The slightly modified literature procedures were used, but starting with previously obtained enamine 2 [34,44]. After the completion of the reaction, the precipitate was formed.…”

“…The solid compound of iodoflavone (3) was pure and used for the next reaction without further purifications. 1 [1,4]dioxin-6-yl)-6,7-dimethoxy-4H-chromen-4-one (5) The previously reported literature procedures were used but starting with the 3-iodo flavone compound (3) [34,45]. For the complete assignment for the proton atoms and carbon atoms, additional two-dimensional NMR such as HMBC (heteronuclear multiple bond correlation), HMQC (heteronuclear multiple-quantum correlation) and TOCSY (total correlation spectroscopy) were performed (Supplementary Materials).…”