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High-throughput assays for drug screening applications have to fulfill particular specifications. Besides the capability to identify even compounds with low potency, one of the major issues is to minimize the number of false-positive hits in a screening campaign in order to reduce the logistic effort for the subsequent cherry picking and confirmation procedure. In this respect, fluorescence lifetime (FLT) appears as an ideal readout parameter that is supposed to be robust against autofluorescent and light-absorbing compounds, the most common source of systematic false positives. The extraordinary fluorescence features of the recently discovered [1,3]dioxolo[4,5-f][1,3]benzodioxole dyes were exploited to develop an FLT-based binding assay with exceptionally robust readout. The assay setup was comprehensively validated and shown to comply not only with all requirements for a powerful high-throughput screening assay but also to be suitable to determine accurate binding constants for inhibitors against enzymes of the histone deacetylase family. Using the described binding assay, the first inhibitors against three members of this enzyme family from Pseudomonas aeruginosa were identified. The compounds were characterized in terms of potency and selectivity profile. The novel ligand probe should also be applicable to other homologues of the histone deacetylase family that are inhibited by N-hydroxy-N'-phenyloctandiamide.
Small fluorescent organic molecules based on [1,3]dioxolo[4,5-f][1,3]benzodioxole (DBD) could be used as probes for lipophillic microenvironments in aqueous solutions by indicating the critical micelles concentration of detergents and staining cell organelles. Their fluorescence lifetime decreases drastically by the amount of water in their direct environment. Therefore they are potential probes for fluorescence lifetime imaging microscopy (FLIM).
A new class of fluorescent dyes based on 1,3-benzodioxole and [1,3]-dioxolo[4.5-f]benzodioxole
(2011)
We report on synthesis and photophysical properties of a new class of fluorescent dyes. They are characterized by large Stokes-shifts, long fluorescence lifetimes in organic solvents and a pronounced dependency of the fluorescence lifetime on the solvent polarity. Also worthy of note is the high bleaching stability. To provide access to biochemical and medical applications a series of derivatives were prepared, which exhibit specific reactivity towards different biologically relevant functional groups (carboxylic acids, amines, maleimides, N-hydroxysuccinimide esters). Furthermore, two alkynes were prepared, which could be used in 'Click' chemistry.