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

Abstract

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, Δ H , Δ S , and Δ G , showing that the tetrandrine derivatives exhibit high affinity toward dsDNA ( K ≈ 10 5 –10 7 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 IC 50 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.

Tetrandrine Derivatives as Promising Antibacterial Agents

“…In this sense, there are some works about tetrandrine derivatives with antiproliferative activity against various tumor cell lines. − However, to the best of our knowledge, there are no reports documenting other biological properties of tetrandrine derivatives. Our research group is a pioneer in the chemical modification of the tetrandrine alkaloid, based on the alkylation of its nitrogen atoms, as well as in the physicochemical and molecular recognition studies of this type of derivatives toward anions of biological importance, such as DNA. − More recently, we have also studied the antiproliferative activity in various cancer cell lines for some of these derivatives. , In this context, the mono- N -substituted derivatives with acridine and anthracene MAcT and ManT , respectively (Figure ), , were shown to have good antiproliferative activity, with an outstanding IC 50 of 2.74 μg/mL for ManT against HeLa cervical cancer cell line, a value 3.3 times lower than that of natural tetrandrine. Furthermore, it was also shown that both derivatives have good affinity toward ds-DNA under physiological conditions.…”

“…Our research group is a pioneer in the chemical modification of the tetrandrine alkaloid, based on the alkylation of its nitrogen atoms, as well as in the physicochemical and molecular recognition studies of this type of derivatives toward anions of biological importance, such as DNA. 27 − 35 More recently, we have also studied the antiproliferative activity in various cancer cell lines for some of these derivatives. 32 , 35 In this context, the mono- N -substituted derivatives with acridine and anthracene MAcT and ManT , respectively ( Figure 1 ), 32 , 33 were shown to have good antiproliferative activity, with an outstanding IC 50 of 2.74 μg/mL for ManT against HeLa cervical cancer cell line, a value 3.3 times lower than that of natural tetrandrine.…”

“… 27 − 35 More recently, we have also studied the antiproliferative activity in various cancer cell lines for some of these derivatives. 32 , 35 In this context, the mono- N -substituted derivatives with acridine and anthracene MAcT and ManT , respectively ( Figure 1 ), 32 , 33 were shown to have good antiproliferative activity, with an outstanding IC 50 of 2.74 μg/mL for ManT against HeLa cervical cancer cell line, a value 3.3 times lower than that of natural tetrandrine. Furthermore, it was also shown that both derivatives have good affinity toward ds-DNA under physiological conditions.…”