4-Alkylsubstituted 3-aryl-cycl[3.2.2]azine-1,2-dicarboxylic acids and their sodium salts as novel π-extended blue-green fluorophores: synthesis, spectroscopy, log D7.4 distribution coefficients and cytotoxicity

Abstract

The family of 3-arylcycl[3.2.2]azine-1,2-dicarboxylic acids has been extended with a series of 4-alkylsubstituted derivatives. The corresponding water-soluble sodium salts were synthesized as well. The obtained compounds are characterized by intense light absorption up to 450 nm (lgε 4–4.5), pronounced blue-green fluorescence in 430–550 nm region (ΦF 10–30 %), good cellular uptake with the values of experimentally determined log D7.4 distribution coefficients ranging from −0.5 to 1.3, and cytotoxicity in HeLa cells classified as weak to moderate (for most of the compounds, IC50 ≥ 100 μM) and being at levels typical of most fluorophores already widely used in molecular imaging. Moreover, a good correlation of cytotoxicity and log D7.4 values has been established implying that cytotoxicity tends to decrease with increasing hydrophilicity of the compounds. Finally, the compounds retain fluorescence after penetration into living cells, distributing discretely in the cytoplasm and perinuclear space, which characterizes them as promising blue-green fluorophores for biomedical applications.