Meso-Substituent-Directed Aggregation Behavior and Water Solubility: Direct Functionalization of Methine Chain in Thiazole Orange and Biological Applications in Aqueous Buffer

A new strategy is presented to preclude aggregation and enhance water solubility of cyanine dyes. Namely, a heteroatom-containing substituent, for distorting molecular plane and increasing interaction with water molecules, is introduced to the methine chain of 2-thiazole orange (1, a monocyanine) via one-step, and 2-thiazole orange derivatives 2a–g are prepared accordingly. The X-ray crystal structures show that the molecular plane of 2a–g is drastically twisted, which reduces intermolecular π–π stacking. The derivatives 2a–g exhibit good to excellent water solubility and can be dissolved in aqueous phosphate-buffered saline (PBS) at concentrations suitable for biomedical applications. No aggregation in aqueous PBS, relatively high molar extinction coefficients, and low solvatochromism of 2a–g are reflected by the UV–vis spectra. Compound 2b shows fast response and high selectivity for biothiols (Cys, Hcy, and GSH) in aqueous PBS and is further employed to detect endogenous biothiols with decent biocompatibility as demonstrated by live cell fluorescence imaging.