Photophysicochemical Properties and In Vitro Phototherapeutic Effects of Iodoquinoline- and Benzothiazole-Derived Unsymmetrical Squaraine Cyanine Dyes

Abstract

The search to replace conventional cancer treatment therapies, such as chemotherapy, radiotherapy and surgery has led over the last ten years, to a substantial effort in the development of several classes of photodynamic therapy photosensitizers with desired photophysicochemical and photobiological properties.Herein we report the synthesis of 6-iodoquinoline-and benzothiazole-based unsymmetrical squaraine cyanine dyes functionalized with amine groups located in the four-membered central ring. Their photodegradation and singlet oxygen production ability, as well as their in vitro photocytotoxicity against Caco-2 and HepG2 cell lines using a 630.8 ± 0.8 nm centered light-emitting diode system, were also investigated. All photosensitizer candidates displayed strong absorption within the tissue transparency spectral region (650-850 nm). The synthesized dyes were found to have moderate light stability. The potential of these compounds is evidenced by their cytotoxic activity against both tumor cell lines, highlighting the zwitterionic unsubstituted dye, which showed more intense photodynamic activity. Although the singlet oxygen quantum yields of these iodinated derivatives are considered low, it could be concluded that their introduction into the quinoline heterocycle was highly advantageous as it played a role in increasing selective cytotoxicity in the presence of light. Thus, the novel synthesized dyes present photophysicochemical and in vitro photobiological properties that make them excellent photosensitizer candidates for photodynamic therapy.

Quinoline- and Benzoselenazole-Derived Unsymmetrical Squaraine Cyanine Dyes: Design, Synthesis, Photophysicochemical Features and Light-Triggerable Antiproliferative Effects against Breast Cancer Cell Lines

“…Nevertheless, their capacity for absorbing energy remained quite high. This finding has been observed previously for other symmetrical and unsymmetrical squaraine cyanine dyes derived from other heterocycles [41,48]. The occurrence of the J-type aggregates formation, as we saw for the aminosquaraine dyes 11 and 12 in specific aqueous media, until then, was not observed by us in other squaraine dyes.…”

“…This signals' duplication can be explained by the difficulty in the free rotation of the bond between the nitrogen atom of N-methylamine substituent and the carbon of the four-membered central ring, occurring from the partial character of the double bond, which should promote the non-equivalence of chemical environments. Our research group recently observed this phenomenon in the NMR spectra of several symmetrical [25,41] and unsymmetrical methylaminosquaraine cyanine dyes [37,48].…”

“…Regarding the dyes' light-stability, an approach that has been explored in our prior studies [25,41,48], the unsubstituted dye in the zwitterionic dye 9 was the one that stood out the most, as it is very stable to light (Figure 3). Aminosquaraine dyes had a worse photostable performance, since there was a more pronounced decrease in the absorbance of dyes 11 and 12 over the irradiation periods.…”

“…Singlet oxygen quantum yields of squaraine dyes 9, 11 and 12 were measured as earlier described by our research group [48]. In summary, a system equipped with a OBB OL-401 nitrogen laser (Horiba Scientific, Piscataway, NJ, USA) exiting at 337 nm with 0.60 ns pulses and 1.1 mJ/pulse, and a detection system with an indium gallium arsenide charge-coupled device (model iDus from Andor Technology Limited, Belfast, UK) working at −60 • C coupled to a fixed spectrograph (model Shamrock 163i also from Andor).…”

“…Among the most common of the structural modifications in squaraine cyanine dyes, the introduction of heavy atoms is noteworthy, since, according to the literature, it leads to an increase in the dyes' ability to generate type II reactions [45,70]. Despite the importance given to singlet oxygen about the potential application of novel molecules in photodynamic therapy, several studies showed that other mechanisms of action may be involved in phototherapeutic activity, namely type I reactions, in which other reactive oxygen species are produced that, despite being less responsive, are also highly toxic agents at high concentrations [37,48].…”