A convenient approach for the direct synthesis of meso-substituted thiazole orange (meso-TO) analogues has been unprecedentedly developed through the AlCl3-catalyzed reaction of parent TO with benzyl alcohol derivatives. Single-crystal X-ray structures show that the prepared new meso-TO analogues are nonplanar, forming a sharp contrast to planar TO. The spectral properties show that nonplanar meso-TO analogues do not aggregate, existing in monomer form (M) in PBS buffer, and have little effect of solvatochromism in different solvents. In comparison with the parents, meso-TO analogues exhibit a large Stokes shift, excellent light fastness, and inertness to singlet oxygen. A cellular association study demonstrates that incorporation of a benzyl group at the meso position methine of parent TO can decrease the cytotoxicity, change staining area in cells, and emit long-wavelength fluorescence for an extended time, which are useful for the development of smarter TOs for imaging in biological science.

The cyanine dye thiazole orange (TO, including 2TO and 4TO) is widely used as a light-up fluorescent probe upon binding to almost all forms of DNA, but it exhibits poor selectivity for recognizing G-quadruplex DNA (G-DNA), which has significant biological functions in biological processes and therapeutic applications. Here, introducing benzyl substituent to the meso position of the methine chain of 2TO is expected to selectively recognize G-DNA. The spectroscopic titrations reveal that modified 2TO ( meso -Bn-2TO) has almost no background fluorescence in solution and shows a preference to bind with G-DNA over ssDNA, dsDNA, and ct-DNA. Specifically, meso -Bn-2TO 1a displays a strong fluorescent signal upon interaction with G-DNA and a very weak fluorescent signal upon interaction with ssDNA, dsDNA, and ct-DNA, displaying considerable selectivity for G-DNA. However, parent 2TO all gives a fluorescent signal in G-DNA, dsDNA, and ct-DNA. The fluorescence intensity of 1a increases nearly 80–162 times when bound with different G-DNA. The binding constants of 1a and 2TO to G-DNA htg22 are 3.16 and 1.52 μM, respectively. Molecular docking study of 1a and 2TO with different DNA reveals that introducing benzyl substituent to the meso position methine chain of 2TO alters the planarity of the chromophore, thus enhancing the interactions with G-DNA and weakening the interactions with duplex DNA and therefore realizing selective detection to G-DNA.

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