Tetrandrine Derivatives as Promising Antibacterial Agents.

This work reports on the antibacterial activity of two tetrandrine derivatives, with acridine (MAcT) and anthracene (MAnT) units, against Gram-positive and Gram-negative bacteria of clinical importance by the broth microdilution method as well as their antioxidant activity against ABTS•+ and DPPH•+ radicals. Unlike natural tetrandrine, its derivatives inhibited bacterial growth, showing selectivity against Staphylococcus aureus with notable activity of MAnT (MIC = 0.035 µg/mL); this compound also has good activity against the ABTS•+ radical (IC50 = 4.59 µg/mL). Cell membrane integrity studies and reactive oxygen species (ROS) detection by fluorescent stains helped to understand possible mechanisms related to antibacterial activity, while electrophoretic mobility assays showed that the derivatives can bind to bacterial DNA plasmid. The results indicate that MAnT can induce a general state of oxidative stress in S. aureus and Escherichia coli, while MAcT induces an oxidative response in S. aureus. Complementary electrochemical studies were included.

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

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.

A Chiral Bis-Naphthylated Tetrandrine Dibromide: Synthesis, Self-Assembly into an Organic Framework Based On Nanosized Spherical Cages, and Inclusion Studies.

Crystalline framework materials have gained interest because of their many potential applications. A novel chiral tetrandrine salt (DNT) has been synthesized and characterized by conventional analytical techniques and single-crystal X-ray diffraction analysis, and its self-assembly behavior studied. In the solid state, 48 molecules of the compound self-assemble into an organic framework based on nanospherical aggregates formed exclusively through weak noncovalent interactions. Additionally, it was demonstrated by UV-vis spectroscopy and TGA that assembled DNT can include the Nile Red dye, giving a fluorescent material. To the best of our knowledge, these spherical assemblies are the largest among the purely synthetic organic self-assembled molecular crystals reported to date.

Synthesis, spectroscopic, physicochemical and structural characterization of tetrandrine-based macrocycles functionalized with acridine and anthracene groups: DNA binding and anti-proliferative activity.

In this work, we report on the synthesis of two new mono-alkylated tetrandrine derivatives with acridine and anthracene units, MAcT and MAnT. The compounds were fully characterized by physicochemical techniques and single-crystal X-ray diffraction analysis. In addition, both derivatives were studied as nucleotide receptors and double-stranded DNA binders in aqueous phosphate buffer at pH = 7.2 using UV-vis and fluorescence spectroscopy. According to the molecular recognition studies, MAcT and MAnT exhibit high affinity (K ∼ 105 M-1) and selectivity for ds-DNA, presumably in an intercalation mode. Finally, the anti-proliferative effects of the tetrandrine derivatives on different cancer cell lines were explored, revealing promising activities. Particularly, the mono-anthracene tetrandrine derivative MAnT showed an IC50 of 2.74 µg/mL on the HeLa cervical cancer cell line, representing a value 3.3 times smaller than that obtained for unsubstituted tetrandrine. Examination of the cytotoxic effects on the HeLa cell line by inverted microscopy suggests that the cell death mechanism consists basically in apoptosis. The molecular modelling of three ds-DNA-MAcT complexes, suggested that the macrocycles may use an intercalation binding mode towards DNA. MAcT is predicted to bind into the major groove of the ds-DNA providing non-covalent interactions such as electrostatic, van der Waals and hydrophobic interactions that lead to selectivity. Overall experimental data supports the mode of action of MAnT and MAcT as cytotoxic compounds against cancer cell lines via a DNA interaction mechanism.