In
this study, we show that fluorescent boronic-acid derived salicylidenehydrazone
complexes (BASHY) can function as fluorescent linkers for bioconjugates
that were used to monitor the delivery of the proteasome inhibitor
bortezomib (Btz) to HT-29 cancer cells. BASHY complexes were structurally
optimized to improve the stability of the complex in buffered conditions
(ammonium acetate, pH 7 up to t
1/2 = 40
h), photophysically characterized regarding their fluorescence properties
and used in confocal microscopy colocalization studies that revealed
their intracellular sequestration by lipid droplets. The accumulation
in these hydrophobic organelles limited the hydrolysis of the complex
and consequently the drug release, a problem that was circumvented
by the conjugation of the BASHY-Btz complex with a cell-penetrating
peptide GV1001-C. The conjugate exhibited an improved cytoplasmic
availability as confirmed by confocal fluorescence microscopy studies
and an improved potency against HT-29 cancer cells (IC50 = 100 nM) as compared to the nontargeted complex (IC50 = 450 nM).
A set of nine boronic‐acid‐derived salicylidenehydrazone (BASHY) complexes has been synthesized in good to very good chemical yields in a versatile three‐component reaction. In an extension to previous reports on this dye platform, the focus was put on the electronic modification of the “vertical” positions of the salicylidenehydrazone backbone. This enabled the observation of fluorescence quenching by photoinduced electron transfer (PeT), which can be reverted by the addition of acid in organic solvent (OFF‐ON fluorescence switching). The resulting emission is observed in the green‐to‐orange spectral region (maxima at 520–590 nm). In contrast, under physiological pH conditions in water, the PeT process is inherently decativated, thereby enabling the observation of fluorescence in the red‐to‐NIR region (maxima at 650–680 nm) with appreciable quantum yields and lifetimes. The latter characteristic supported the application of the dyes in fluorescence lifetime imaging (FLIM) of live A549 cells.
BASHY dyes, such as the one drawn in the foreground, are prepared in a multicomponent reaction. This is symbolized by the background, which shows part of a beach that is made of sea‐washed stones and which is located in the North of Portugal (Praia de Belinho). The BASHY dyes discussed in the Research Article by P. M. P. Gois, U. Pischel and co‐workers (DOI: 10.1002/chem.202300579) show several photophysical features such as fluorescence, intramolecular charge transfer (ICT), and photoinduced electron transfer (PeT), which jointly orchestrate the function of the dye.
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