Urea-thiazole/benzothiazole hybrids with a triazole linker: synthesis, antimicrobial potential, pharmacokinetic profile and in silico mechanistic studies.

Some urea-thiazole/benzothiazole hybrids with a triazole linker were synthesized via Cu(I)-catalysed click reaction. After successfully analysed by various spectral techniques including FTIR, NMR and HRMS, antimicrobial screening of the synthesized hybrids along with their precursors was carried out against two Gram (+) bacteria (Staphylococcus aureus and Bacillus endophyticus), two Gram (-) bacteria (Escherichia coli and Pseudomonas fluorescens) and two fungi (Candida albicans and Rhizopus oryzae). All the synthesized compounds (4a-4l) displayed better biological response than the standard fluconazole against both of the tested fungi. Compounds 4h and 4j were found to be the most active compounds against R. oryzae and C. albicans, respectively. Molecular docking of hybrid 4j and its alkyne precursor 1b in the active site of C. albicans target sterol 14-α demethylase was also performed and was also supported by molecular dynamics studies. In silico ADME prediction of synthesized urea-thiazole/benzothiazole hybrids with a triazole linker and their alkyne precursors was also predicted.

Identification of Tumor Initiating Cells with a Small-Molecule Fluorescent Probe by Using Vimentin as a Biomarker.

Tumor initiating cells (TICs) have been implicated in clinical relapse and metastasis of a variety of epithelial cancers, including lung cancer. While efforts toward the development of specific probes for TIC detection and targeting are ongoing, a universal TIC probe has yet to be developed. We report the first TIC-specific fluorescent chemical probe, TiY, with identification of the molecular target as vimentin, a marker for epithelial-to-mesenchymal transition (EMT). TiY selectively stains TICs over differentiated tumor cells or normal cells, and facilitates the visualization and enrichment of functionally active TICs from patient tumors. At high concentration, TiY also shows anti-TIC activity with low toxicity to non-TICs. With the unexplored target vimentin, TiY shows potential as a first universal probe for TIC detection in different cancers.

Detection of Pathogenic Biofilms with Bacterial Amyloid Targeting Fluorescent Probe, CDy11.

Bacterial biofilms are responsible for a wide range of persistent infections. In the clinic, diagnosis of biofilm-associated infections relies heavily on culturing methods, which fail to detect nonculturable bacteria. Identification of novel fluorescent probes for biofilm imaging will greatly facilitate diagnosis of pathogenic bacterial infection. Herein, we report a novel fluorescent probe, CDy11 (compound of designation yellow 11), which targets amyloid in the Pseudomonas aeruginosa biofilm matrix through a diversity oriented fluorescent library approach (DOFLA). CDy11 was further demonstrated for in vivo imaging of P. aeruginosa in implant and corneal infection mice models.

Chemical Fluorescent Probe for Detection of Aß Oligomers.

Aggregation of amyloid ß-peptide (Aß) is implicated in the pathology of Alzheimer's disease (AD), with the soluble, Aß oligomeric species thought to be the critical pathological species. Identification and characterization of intermediate species formed during the aggregation process is crucial to the understanding of the mechanisms by which oligomeric species mediate neuronal toxicity and following disease progression. Probing these species proved to be extremely challenging, as evident by the lack of reliable sensors, due to their heterogeneous and transient nature. We describe here an oligomer-specific fluorescent chemical probe, BoDipy-Oligomer (BD-Oligo), developed through the use of the diversity-oriented fluorescent library approach (DOFLA) and high-content, imaging-based screening. This probe enables dynamic oligomer monitoring during fibrillogenesis in vitro and shows in vivo Aß oligomers staining possibility in the AD mice model.

A highly selective fluorescent probe for direct detection and isolation of mouse embryonic stem cells.

Stem cell research has gathered immense attention in the past decade due to the remarkable ability of stem cells for self-renewal and tissue-specific differentiation. Despite having numerous advancements in stem cell isolation and manipulation techniques, there is a need for highly reliable probes for the specific detection of live stem cells. Herein we developed a new fluorescence probe (CDy9) with high selectivity for mouse embryonic stem cells. CDy9 allows the detection and isolation of intact stem cells with marginal impact on their function and capabilities.

The small molecule probe PT-Yellow labels the renal proximal tubules in zebrafish.

We report the development of a small fluorescent molecule, BDNCA3-D2, herein referred to as PT-Yellow. Soaking zebrafish embryos in PT-Yellow or intraperitoneal injection into adults results in non-toxic in vivo fluorescent labeling of the renal proximal tubules, the major site of blood filtrate reabsorption and a common target of injury in acute kidney injury. We demonstrate the applicability of this new compound as a rapid and simple readout for zebrafish kidney filtration and proximal tubule reabsorption function.

Synthesis and systematic evaluation of dark resonance energy transfer (DRET)-based library and its application in cell imaging.

In this paper, we report a new strategy for constructing a dye library with large Stokes shifts. By coupling a dark donor with BODIPY acceptors of tunable high quantum yield, a novel dark resonance energy transfer (DRET)-based library, named BNM, has been synthesized. Upon excitation of the dark donor (BDN) at 490 nm, the absorbed energy is transferred to the acceptor (BDM) with high efficiency, which was tunable in a broad range from 557 nm to 716 nm, with a high quantum yield of up to 0.8. It is noteworthy to mention that the majority of the non-radiative energy loss of the donor was converted into the acceptor's fluorescence output with a minimum leak of donor emission. Fluorescence imaging tested in live cells showed that the BNM compounds are cell-permeable and can also be employed for live-cell imaging. This is a new library which can be excited through a dark donor allowing for strong fluorescence emission in a wide range of wavelengths. Thus, the BNM library is well suited for high-throughput screening or multiplex experiments in biological applications by using a single laser excitation source.

Live cells imaging using a turn-on FRET-based BODIPY probe for biothiols.

We designed a red-emitting turn-on FRET-based molecular probe 1 for selective detection of cysteine and homocysteine. Probe 1 shows significant fluorescence enhancement after cleavage of the 2, 4-dinitrobenzensulfonyl (DNBS) unit from the fluorophore upon thiols treatment. The precursor of probe 1, BNM153, is a moderate quantum yield FRET dye which contributes a minimum emission leakage from its donor part. We synthesized this assembly by connecting a low quantum yield (less than 1%) BODIPY donor to a high quantum yield BODIPY acceptor via a 1, 3-triazine bridge system. It is noteworthy that the majority of the non-radiative energy loss of donor (BDN) was converted to the acceptor (BDM)'s fluorescence output with minimum leaks of donor emission. The fluorescence sensing mechanism of probe 1 was illustrated by fluorescence spectroscopy, kinetic measurements, HPLC-MS analysis and DFT calculations. Probe 1 is pH-independent at the physiological pH range. Finally, live cells imaging demonstrated the utility of probe 1 as a biosensor for thiols.

Hierarchical organization from self-assembling disulfide macrocycles.

We report cystine-based macrocyclic compounds showing very unique self-assembling behavior. 24-membered disulfide macrocycle 3 shows a helical and tubular organization and also forms an insoluble plaque that is birefringent with congo red dye. 48-membered macrocycle 4 shows a vesicle-like assembly with capability for encapsulation, as demonstrated by rhodamine B encapsulation.