Structure-Based Discovery of High-Affinity Small Molecule Ligands and Development of Tool Probes to Study the Role of Chitinase-3-Like Protein 1.

Chitinase-3-like-1 (CHI3L1), also known as YKL-40, is a glycoprotein linked to inflammation, fibrosis, and cancer. This study explored CHI3L1's interactions with various oligosaccharides using microscale thermophoresis (MST) and AlphaScreen (AS). These investigations guided the development of high-throughput screening assays to assess interference of small molecules in binding between CHI3L1 and biotinylated small molecules or heparan sulfate-based probes. Small molecule binders of YKL-40 were identified in our chitotriosidase inhibitors library with MST and confirmed through X-ray crystallography. Based on cocrystal structures of potent hit compounds with CHI3L1, small molecule probes 19 and 20 were designed for an AS assay. Structure-based optimization led to compounds 30 and 31 with nanomolar activities and drug-like properties. Additionally, an orthogonal AS assay using biotinylated heparan sulfate as a probe was developed. The compounds' affinity showed a significant correlation in both assays. These screening tools and compounds offer novel avenues for investigating the role of CHI3L1.

Nickelacyclic-cobaltocene vs. nickelacyclic-nickelocene. Synthesis, X-ray structures, electron transfer activity, EPR spectroscopy, and theoretical calculations.

Reactions of 9-nickelafluorenyllithium with cobalt and nickel pentamethylcyclopentadienyl-acetylacetonates resulted in the formation of the novel nickelacyclic-cobaltocene 2 and nickelacyclic-nickelocene 3, respectively, in which the central metal atom is bonded to the nickelafluorenyl ring. On the basis of their redox propensity, compounds 2 and 3 were oxidized to the corresponding monocations [2](+) and [3](+). The crystal and molecular structures of both the redox couples were determined by single-crystal X-ray analysis. In spite of their structural similarity, they display a rather different electron transfer ability. To throw light on such an aspect, the pertinent redox couples have been examined by EPR spectroscopy and the nature of the frontier orbitals involved in the redox activity of the neutral precursors has been supported by extended Huckel theoretical calculations.

Electron transfer activity of nickelacyclic complex analogues of nickelocene: synthesis of (eta(5)-R-cyclopentadienyl){eta(4)-[1-(eta(5)-R-cyclopentadienyl)]-2,3,4,5-tetraphenyl-1-nickela-2-cyclopentenyl}nickel complexes (R = H, CH(3)) and crystal structures of the redox couples [(eta(5)- methylcyclopentadienyl){eta(4)-[1-(eta(5)-methylcyclopentadienyl)]-2,3,4,5-tetraphenyl-1-nickela-2-cyclopentenyl}nickel]((0/+)) and [(eta(5)-methylcyclopentadienyl){eta(5)-[1-(eta(5)-methylcyclopentadienyl)-1-nickelafluorenyl}nickel]((0/+)).

Following previous reports on the synthesis and structure of different nickelacyclic complexes analogues of nickelocene, we now deal with the new metallacyclic compounds (eta5-R-cyclopentadienyl){eta4-[1-(eta5-R-cyclopentadienyl)]-2,3,4,5-tetraphenyl-1-nickela-2-cyclopentenyl}nickel (R = H, CH3). The redox ability of the whole series of nickelacyclic derivatives has been also investigated by electrochemical and spectroelectrochemical techniques, and the nature of the frontier orbitals responsible for the rich electron transfer activity of this class of compounds has been supported by theoretical considerations. On the basis of the redox properties of a few neutral members of the series, their chemical oxidation afforded the corresponding monocations and the crystal structures of the pertinent redox couples were determined by X-ray single-crystal analysis.