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Abstract Aurora kinases play critical roles in the regulation of the cell cycle and mitotic spindle assembly. Aurora A kinase, a member of the Aurora protein family, is frequently highly expressed in tumors, and selective Aurora A inhibition serves as a significant component of anticancer therapy. However, designing highly selective Aurora A inhibitors is difficult because Aurora A and B share high homology and differ only by three residues in their ATP-binding pockets. Through structure-based drug design, we designed and synthesized a series of novel quinazolin-4-amine derivatives. These derivatives act as selective Aurora A kinase inhibitors by exploiting the structural differences between Aurora A and B. The selectivities of most compounds were improved (the best up to >757-fold) when comparing with the lead compound (3-fold). In vitro biochemical and cellular assays revealed that compound 6 potently inhibited Aurora A kinase and most human tumor cells. Furthermore, compound 6 effectively suppressed carcinoma, such as triple-negative breast cancers (TNBC) in an animal model. Therefore, compound 6 might serve as a promising anticancer drug. Moreover, through molecular dynamic (MD) analysis, we have identified that a salt bridge formed in Aurora B is key contributor for the isoform selectivity of the inhibitor. This salt bridge has not been previously detected in the reported crystal structure of Aurora B. These results might provide a crucial basis for the further development of highly potent inhibitors with high selectivity for Aurora A. Graphical abstract Image 1 Highlights • A series of quinazolin-4-amine derivatives as selective Aurora A kinase inhibitors were synthesized. • The selectivities of most compounds were improved (the best up to >757-fold). • Compound 6 potently inhibited Aurora A kinase, human tumor cells and triple-negative breast cancers (TNBC) in animal model. • A salt bridge formed in Aurora B is key contributor for the isoform selectivity of the inhibitor. [ABSTRACT FROM AUTHOR]

A novel metal-free D-π-A-π-A based organic photosensitizer, with carbazole as electron donor; benzothiadiazole as auxiliary electron withdrawing unit; acetylene and benzene as linker; and cyanoacrylic acid as anchoring group, has been successfully synthesized and effectively employed in the development of solar energy conversion of photovoltaic devices and solar hydrogen generation. In the solar energy conversion systems, comparisons were made with a simple reference D-π-A sensitizer. The results show that the new D-π-A-π-A dye has greater potential in the light-to-fuel conversion (Φ H2 = 5.56% for the new dye vs Φ H2 = 0.12% for the reference dye) than light-to-electricity conversion ( η = 3.50% for the new dye vs 1.14% for the reference dye). [ABSTRACT FROM AUTHOR]

The increasing antibiotic resistance driven by Pseudomonas aeruginosa typically leads to uncontrolled and persistent inflammatory damage, which is primarily attributed to the virulence and biofilms produced by the bacteria. Herein, we present a novel anti-infective drug strategy designed to inhibit the bacterial quorum sensing system, thereby attenuating P. aeruginosa virulence, and modulating inflammation from drug-resistant bacterial infections. We discovered new quorum sensing LasR/LasB inhibitors derived from the structural modification of a ligustilide derivative library. Of these compounds, 5f demonstrated significant inhibitory activity against LasB (LasB-gfp, IC 50 = 8.7 μM) and a moderate inhibitory effect on P. aeruginosa biofilms (IC 50 = 7.4 μM). Through live image analysis in a fluorescent protein–labeled zebrafish larva model, we observed that compound 5f significantly inhibited the migration of macrophages. Moreover, compound 5f effectively attenuated quorum sensing–mediated virulence factors and biofilm formation by P. aeruginosa. It also alleviated the inflammatory response by P. aeruginosa –infected macrophages through the downregulation of mitogen-activated protein kinase and NF-κB signal-transduction pathways. Notably, in vivo experiments, this compound demonstrated marked therapeutic effects in acute lung injury models induced by lipopolysaccharides from P. aeruginosa. These results indicate that compound 5f has the potential to be a novel anti-infective candidate against drug-resistant infections caused by P. aeruginosa. [Display omitted] • A series of ligustilide derivatives were synthesized. • Compound 5f with excellent P. aeruginosa virulence, biofilm, inflammatory inhibitory effect was identified. • 5f significantly attenuated QS-controlled virulence factors, P. aeruginosa biofilm formation, and the inflammatory response in P. aeruginos a–infected macrophages by downregulating MAPK and NF-κB signal-transduction pathways. • Novel potential anti-infective LasR/LasB inhibitor of 5f with superior anti-biofilm, anti-inflammatory, and anti-virulence activities, making it a promising candidate for combating drug-resistant bacterial infections. [ABSTRACT FROM AUTHOR]

This study focuses on preparation and structural investigation of the water insoluble Keratin/poly (ethylene oxide) (PEO) blend nanofiber mat with high content of keratin for biomedical utilization. A modified secondary crosslinking process in oxygen atmosphere was first employed to improve the water insolubility of the electrospun keratin/PEO nanofibers with high keratin content, following the primary crosslinking process with ethylene glycol diglycidyl ether (EGDE), for cell culture. A systematic quantitative analysis of liquid viscosity, FTIR, XRD, and TG were conducted to illustrate the electrospinnability of the primary crosslinked keratin/PEO blend water solution and the water insolubility of the secondary crosslinked nanofiber mat. The results indicated that the increase of the keratin molecular weight by the primary crosslinking reaction between keratin molecules by EGDE might be the main reason for the improved electrospinnability of the solution. The water insolubility of the secondary crosslinked nanofiber mat was attributed to the rebuilt of the sulfur crosslinking bonds between keratin formed in pure oxygen atmosphere during the secondary crosslinking process. The biocompatibility of the water insoluble keratin/PEO blend nanofiber mat was also investigated with cell cultivation, suggesting the nanofibers had a potential in tissue engineering and biomaterials field. [ABSTRACT FROM AUTHOR]