DNA-Binding Properties of Bis-N-substituted Tetrandrine Derivatives

Sandra Mónica González-Martínez, Drochss Pettry Valencia-Ochoa, Juan Carlos Gálvez-Ruiz, Mario Alberto Leyva-Peralta, Octavio Juárez-Sánchez, María A. Islas-Osuna, Viviana Isabel Calvillo-Páez, Herbert Höpfl, Ramón Íñiguez-Palomares, Fernando Rocha-Alonzo, Karen Ochoa Lara*

*Autor correspondiente de este trabajo

Resultado de la investigación: Contribución a una revistaArtículorevisión exhaustiva

Resumen

A series of bis-N-substituted tetrandrine derivatives carrying different aromatic substituents attached to both nitrogen atoms of the natural alkaloid were studied with double-stranded model DNAs (dsDNAs) to examine the binding properties and mechanism. Variable-temperature molecular recognition studies using UV-vis and fluorescence techniques revealed the thermodynamic parameters, ΔH, ΔS, and ΔG, showing that the tetrandrine derivatives exhibit high affinity toward dsDNA (K ≈ 105-107 M-1), particularly the bis(methyl)anthraquinone (BAqT) and bis(ethyl)indole compounds (BInT). Viscometry experiments, ethidium displacement assays, and molecular modeling studies enabled elucidation of the possible binding mode, indicating that the compounds exhibit a synergic interaction mode involving intercalation of one of the N-aryl substituents and interaction of the molecular skeleton in the major groove of the dsDNA. Cytotoxicity tests of the derivatives with tumor and nontumor cell lines demonstrated low cytotoxicity of these compounds, with the exception of the bis(methyl)pyrene (BPyrT) derivative, which is significantly more cytotoxic than the remaining derivatives, with IC50 values against the LS-180, A-549, and ARPE-19 cell lines that are similar to natural tetrandrine. Finally, complementary electrochemical characterization studies unveiled good electrochemical stability of the compounds.

Idioma originalInglés
PublicaciónACS Omega
DOI
EstadoPublicada - 3 may 2022

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© 2022 The Authors. Published by American Chemical Society.

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