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.
Bibliographical noteFunding Information:
This work received financial support from Consejo Nacional de Ciencia y Tecnología Mexico in the form of graduate grants for S.G.M. and V.C.P. and through project Nos. CB-239581 and 281251 (Red Temática de Química Supramolecular). M.A.I.O. thanks Universidad de Sonora for the sabbatical leave support. D.P.V. received financial support from OMICAS program, sponsored within the Colombian Scientific Ecosystem by The World Bank, The Ministry of Science, Technology and Innovation (MINCIENCIAS), ICETEX, the Colombian Ministry of Education, and the Colombian Ministry of Industry and Tourism under Grant ID FP44842-217-2018.
© 2022 The Authors. Published by American Chemical Society.