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. 2023 Jun 1;28(11):4499.
doi: 10.3390/molecules28114499.

The Benzothiazine Core as a Novel Motif for DNA-Binding Small Molecules

Affiliations

The Benzothiazine Core as a Novel Motif for DNA-Binding Small Molecules

Milena Mlakić et al. Molecules. .

Abstract

A new series of 4H-1,3-benzothiazine dyes were prepared and fully characterized in an aqueous medium. Benzothiazine salts were synthesized either through the classical synthetic pathway using Buchwald-Hartwig amination or through economical and environmentally friendly electrochemical synthesis. The latest synthetic approach employs successful electrochemical intramolecular dehydrogenative cyclization of N-benzylbenzenecarbothioamides to form 4H-1,3-benzothiazines. 4H-1,3-Benzothiazines were evaluated as novel DNA/RNA probes. Through the use of several methods such as UV/vis spectrophotometric titrations, circular dichroism and thermal melting experiments, the binding of four benzothiazine-based molecules to polynucleotides was examined. Compounds 1 and 2 acted as DNA/RNA groove binders, thus suggesting the potential of these compounds as novel DNA/RNA probes. This is a proof-of-concept study and will be expanded to include SAR/QSAR studies.

Keywords: 4H-1,3-benzothiazines; DNA/RNA binding; UV/vis spectroscopy; circular dichroism; electrochemical dehydrogenative cyclization.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Reaction pathway for the synthesis of benzothiazines 1 and 2.
Scheme 2
Scheme 2
Reaction pathway for the synthesis of benzothiazines 3, 4 and 8.
Scheme 3
Scheme 3
Structure of compounds 1′ and 2′.
Scheme 4
Scheme 4
Structure of compounds 3′ and 4′.
Scheme 5
Scheme 5
Structure of compounds 1 and 2.
Scheme 6
Scheme 6
Structure of compounds 3 and 4.
Scheme 7
Scheme 7
Structure of compounds 8′ and 8.
Figure 1
Figure 1
Aromatic parts of the 1H NMR spectra (CDCl3) of benzothiazines 1 (a) and 2 (b).
Figure 2
Figure 2
Molecular structure of compound 8′. Displacement ellipsoids are drawn for the probability of 20% and hydrogen atoms are shown as spheres of arbitrary radii.
Figure 3
Figure 3
Crystal packing of 8′ is characterized by hydrogen bonds and stacking interactions.
Figure 4
Figure 4
UV/vis spectra of studied compounds (c = 1 × 10−5 M) in water.
Figure 5
Figure 5
(a) Changes in the UV/vis spectra of 2 (c = 2 × 10−5 M) upon titration with ct-DNA, inset: absorbance changes at λmax = 403 nm, fitted to Scatchard eq. (red line) [21]; (b) normalized absorbance changes at the respective λmax for all studied compounds upon titration with ct-DNA, fitted to Scatchard eq. (red line) [21]; (c) normalized absorbance changes at the respective λmax for all studied compounds upon titration with pApU, fitted to Scatchard eq. (red line) [21].
Figure 6
Figure 6
CD titration of pApU (c = 2 × 10−5 M) with 1 and 2 at molar ratios r = [compound]/[polynucleotide] (pH 7.0, buffer sodium cacodylate, I = 0.05 M). (a) pApU with 1, inset: ICD at 440 nm, (b) pApU with 2, inset: ICD at 410 nm.

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