Abstract
We have designed and synthesized a series of novel, supramolecular, long-lived fluorescent probes based on the host-guest inclusion complexes formation between fluorescent indolizinyl-pyridinium salts and β-cyclodextrin. Fluorescence and electrospray ionisation mass spectrometry experiments, supported by theoretical molecular docking studies, were utilized in the monitoring of the inclusion complexes formation, evidencing the appearance of corresponding 1:1 and 1:2 species. Additionally, the influence of the guest molecule over the aggregation processes of the cyclodextrin inclusion complexes was investigated by transmission electron microscopy. The absence of cytotoxicity, cellular permeability, long-lived intracellular fluorescence, and in time specific accumulation within acidic organelles identified the investigated supramolecular entities as remarkable candidates for intracellular fluorescence probes. Co-staining experiments using specific organelle markers revealed the fact that, after a 24-h incubation period, the inclusion complexes accumulate predominantly in lysosomes rather than in mitochondria. This study opens new possibilities for a broad range of fluorescent dyes with solubility and high toxicity issues, able to form inclusion complexes with β-cyclodextrin, to be tested as intracellular fluorescence probes.
Highlights
The distinctive ability of cyclodextrins (CDs) to form host–guest inclusion complexes with small lipophilic molecules or polymers has attracted the attention of researchers during the last four decades [1,2,3,4,5]
In order to investigate the influence of the guest indolizinyl-pyridinium salt derivatives on the CD complexes aggregation, and to extend the collection of fluorescent pH sensitive CD host–guest probes, we have synthesized three fluorescent indolizinyl-pyridinium salts 1(a–c) (Scheme 1) containing various substituents at the marginal phenyl moieties
Compounds 1(a–c) were synthesized in moderate yields in an adopted two step synthesis based on our methodological background in the preparation of substituted indolizines [31,32,33]
Summary
The distinctive ability of cyclodextrins (CDs) to form host–guest inclusion complexes with small lipophilic molecules or polymers has attracted the attention of researchers during the last four decades [1,2,3,4,5]. Besides the inclusion complex formation, both CDs and CD inclusion complexes may self-assemble in aqueous solutions into nano or micro aggregates by means of weak hydrogen bonds and hydrophobic forces [11,15,16,17]. A large variety of aggregation shapes, including micelles [16], tubes [18], rods [19,20], or discs [21], have been extensively investigated by microscopic methods, such as scanning tunneling microscopy, atomic force microscopy, transmission electron microscopy (TEM), and scanning electron microscopy [22]. The interest in CD complexes aggregates and in the self-aggregation mechanism is explained by their potential applications as candidates for complex drug delivery systems, functional materials, or molecular devices [23,24,25]
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