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

• Main Authors: Soon Young Shin, Young Han Lee, Yoongho Lim, Ha Jin Lee, Ji Hye Lee, Miri Yoo, Seunghyun Ahn, Dongsoo Koh
• Format: Article
• Language: English
• Published: MDPI AG 2020-10-01
• Series: Crystals
• Subjects: disordered crystal structure; hydrogen bonding; in silico docking; Hirshfeld surface; NF-κB signaling; IKKβ inhibitor
• Online Access: https://www.mdpi.com/2073-4352/10/10/911

The structure of the isoflavone compound, 3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6,7-dimethoxy-4H-chromen-4-one (<b>5</b>), was elucidated by 2D-NMR spectra, mass spectrum and single crystal X-ray crystallography. Compound <b>5</b>, C₁₉H₁₆O₆, was crystallized in the monoclinic space group <i>P</i>2₁/c with the cell parameters; a = 12.0654(5) Å, b =11.0666(5) Å, c = 23.9550(11) Å, <i>β</i> = 101.3757(16)°, V = 3135.7(2) ų, and Z = 8. The asymmetric unit of compound <b>5</b> consists of two independent molecules <b>5I</b> and <b>5II</b>. Both molecules exhibit the disorder of each methylene group present in their 1,4-dioxane rings with relative occupancies of 0.599(10) (<b>5I</b>) and 0.812(9) (<b>5II</b>) for the major component <b>A</b>, and 0.401(10) (<b>5I</b>) and 0.188(9) (<b>5II</b>) for the minor component <b>B</b>, respectively. Each independent molecule revealed remarkable discrepancies in bond lengths, bond angles and dihedral angles in the disordered regions of 1,4-dioxane rings. The common feature of the molecules <b>5I</b> and <b>5II</b> are a chromone ring and a benzodioxin ring, which are more tilted towards each other in <b>5I</b> than in <b>5II</b>. An additional difference between the molecules is seen in the relative disposition of two methoxy substituents. In the crystal, the molecule <b>5II</b> forms inversion dimers which are linked into chains along an <i>a</i>-axis direction by intermolecular C–H⋯O interactions. Additional C–H⋯O hydrogen bonds connected the molecules <b>5I</b> and <b>5II</b> each other to form a three-dimensional network. Hirshfeld surface analysis evaluated the relative intermolecular interactions which contribute to each crystal structure <b>5I</b> and <b>5II</b>. Western blot analysis demonstrated that compound <b>5</b> inhibited the TNFα-induced phosphorylation of IKKα/β, resulting in attenuating further downstream NF-κB signaling. A molecular docking study predicted the possible binding of compound <b>5</b> to the active site of IKKβ. Compound <b>5</b> showed an inhibitory effect on the clonogenicity of HCT116 human colon cancer cells. These results suggest that compound <b>5</b> can be used as a platform for the development of an anti-cancer agent targeting IKKα/β.