Search for: All records

In this work, we have taken a donor–acceptor–donor (D–A–D) fluorophore ( II-EDOT-TPA ) and encapsulated it using a linear dendritic block copolymer (LDBC). In parallel, a polyethylene glycol derivative ( PEG-II-EDOT-TPA ) was synthesized. The self-assembly and colloidal properties of both nanoaggregates were comparatively assessed. Photophysical and morphological characterization of the LDBC encapsulated II-EDOT-TPA and PEG-II-EDOT-TPA nanoaggregates was performed, which showed the photophysical and morphological properties differed greatly when comparing the two. Both nanoaggregate types were incubated with HEK-293 cells in order to measure cell viability and perform confocal fluorescence microscopy. Minimal cytotoxicity values (<20%) were seen with the two nanoaggregate forms, while both types of nanoaggregates were found to accumulate into the lysosomes of the HEK-293 cells. This work provides fascinating insights into NIR fluorophore design and methods to effectively alter the photophysical and morphological properties of the nanoaggregates for bio-imaging purposes. 

Guided by computational analysis, herein we report the design, synthesis and evaluation of four novel diazine-based histone deacetylase inhibitors (HDACis). The targets of interest (TOI) are analogues of panobinostat, one of the most potent and versatile HDACi reported. By simply replacing the phenyl core of panobinostat with that of a diazine derivative, docking studies against HDAC2 and HDAC8 revealed that the four analogues exhibit inhibition activities comparable to that of panobinostat. Multistep syntheses afforded the visualized targets TOI1 , TOI2 , TOI3-rev and TOI4 whose biological evaluation confirmed the strength of HDAC8 inhibition with TOI4 displaying the greatest efficacy at varying concentrations. The results of this study lay the foundation for future design strategies toward more potent HDACis for HDAC8 isozymes and further therapeutic applications for neuroblastoma. 

Abstract Histone Deacetylases (HDACs) are an important family of 18 isozymes, which are being pursued as drug targets for many types of disorders. HDAC2 and HDAC8 are two of the isozymes, which have been identified as drug targets for the design of anti‐cancer, neurodegenerative, immunological, and anti‐parasitic agents. Design of potent HDAC2 and HDAC8 inhibitors will be useful for the therapeutic advances in many disorders. This work was undertaken to develop potent HDAC2 and HDAC8 inhibitors. A docking study was performed comparing panobinostat derivatives in both HDAC2 and HDAC8. Six of our derivatives showed stronger binding to HDAC2 than panobinostat, and two of our derivatives showed stronger binding to HDAC8 than panobinostat. We evaluated the molecular features, which improved potency of our inhibitors over panobinostat and also identified another molecular consideration, which could be used to enhance histone deacetylase inhibitor (HDACi) selectivity towards either the HDAC2 or HDAC8 isozymes. The results of this work can be used to assist future design of more potent and selective HDACi for HDAC2 and HDAC8.