Benz[e]indole-bearing aminosquaraine dyes: Which of the amines introduced into the squaric ring will be able to induce the best in vitro photodynamic effect?

Abstract

The introduction of amines into the four-membered central ring of squaraine dyes has proven to be a good way to improve certain attributes of the molecules such as their aqueous solubility, their absorption at higher wavelengths, as well as inducing a more effective interaction with certain biological targets. Therefore this chemical modification has been studied regarding their application in the development of potential photosensitizers for photodynamic therapy. This work presents the synthesis of several N-ethyl chain benz[e]indole-based aminosquaraine dyes with amines of increasing complexity (amino < methylamino < dimethylamino < hydroxyethylamino < hydroxyethylmethylamino < bis(hydroxyethyl)amino), in order to understand the effect of small modifications in the chemical structure on the photobiological activity of these compounds. Within the group of compounds prepared and evaluated, amino- and hydroxyethylamino-bearing dyes were the ones that showed the most interesting in silico and cytotoxicity assay results: low free binding energies for human serum albumin protein, especially hydroxyethylamino for Sudlow site I (−13.58 kcal/mol); higher rates of photocytotoxicity (4–48 times more toxic in the presence of light, depending on the tumor cell line under study) and reasonable rates of tumor selectivity (up to approximately 10 times more photocytotoxic to tumor cells compared to the effects on normal cells). Further studies involving the most promising dyes demonstrated that they are somehow linked or internalized in the mitochondria, that they are little genocytotoxic even after irradiation, that apoptosis, although it occurs, should not be the preferred death mechanism after photodynamic treatment and that a slight increase in the number of cells in the G2/M phase was perceived.