Experimental and Computational Investigation of the Oxime Bond Stereochemistry in c-Jun N-terminal Kinase 3 Inhibitors 11H-Indeno[1,2-b]quinoxalin-11-one Oxime and Tryptanthrin-6-oxime.

11H-Indeno[1,2-b]quinoxalin-11-one oxime (IQ-1) and tryptanthrin-6-oxime are potent c-Jun N-terminal kinase 3 (JNK-3) inhibitors demonstrating neuroprotective, anti-inflammatory and anti-arthritic activity. However, the stereochemical configuration of the oxime carbon-nitrogen double bond (E- or Z-) in these compounds was so far unknown. In this contribution, we report the results of the determination of the double bond configuration in the solid state by single crystal X-ray diffraction and in solution by 1D and 2D NMR techniques and DFT calculations. It was found that both in the solid state and in solution, IQ-1 adopts the E-configuration stabilized by intermolecular hydrogen bonds, in contrast to previously assumed Z-configuration that could be stabilized only by an intramolecular hydrogen bond.

Coordination Polymers Based on Highly Emissive Ligands: Synthesis and Functional Properties.

Coordination polymers are constructed from metal ions and bridging ligands, linking them into solid-state structures extending in one (1D), two (2D) or three dimensions (3D). Two- and three-dimensional coordination polymers with potential voids are often referred to as metal-organic frameworks (MOFs) or porous coordination polymers. Luminescence is an important property of coordination polymers, often playing a key role in their applications. Photophysical properties of the coordination polymers can be associated with intraligand, metal-centered, guest-centered, metal-to-ligand and ligand-to-metal electron transitions. In recent years, a rapid growth of publications devoted to luminescent or fluorescent coordination polymers can be observed. In this review the use of fluorescent ligands, namely, 4,4'-stilbenedicarboxylic acid, 1,3,4-oxadiazole, thiazole, 2,1,3-benzothiadiazole, terpyridine and carbazole derivatives, naphthalene diimides, 4,4',4''-nitrilotribenzoic acid, ruthenium(II) and iridium(III) complexes, boron-dipyrromethene (BODIPY) derivatives, porphyrins, for the construction of coordination polymers are surveyed. Applications of such coordination polymers based on their photophysical properties will be discussed. The review covers the literature published before April 2020.

Arene-Ruthenium(II) Complexes Containing 11H-Indeno[1,2-b]quinoxalin-11-one Derivatives and Tryptanthrin-6-oxime: Synthesis, Characterization, Cytotoxicity, and Catalytic Transfer Hydrogenation of Aryl Ketones.

A series of novel mono- and binuclear arene-ruthenium(II) complexes [(p-cym)Ru(L)Cl] containing 11H-indeno[1,2-b]quinoxalin-11-one derivatives or tryptanthrin-6-oxime were synthesized and characterized by X-ray crystallography, IR, NMR spectroscopy, cyclic voltammetry, and elemental analysis. Theoretical calculations invoking singlet state geometry optimization, solvation effects, and noncovalent interactions were done using density functional theory (DFT). DFT calculations were also applied to evaluate the electronic properties, and time-dependent DFT was applied to clarify experimental UV-vis results. Cytotoxicity for cancerous and noncancerous human cell lines was evaluated with cell viability MTT assay. Complexes demonstrated a moderate cytotoxic effect toward cancerous human cell line PANC-1. The catalytic activity of the complexes was evaluated in transfer hydrogenation of aryl ketones. All complexes exhibited good catalytic activity and functional group tolerance.

Synthesis, biological evaluation, and molecular modeling of 11H-indeno[1,2-b]quinoxalin-11-one derivatives and tryptanthrin-6-oxime as c-Jun N-terminal kinase inhibitors.

c-Jun N-terminal kinases (JNKs) play a central role in many physiologic and pathologic processes. We synthesized novel 11H-indeno[1,2-b]quinoxalin-11-one oxime analogs and tryptanthrin-6-oxime (indolo[2,1-b]quinazoline-6,12-dion-6-oxime) and evaluated their effects on JNK activity. Several compounds exhibited sub-micromolar JNK binding affinity and were selective for JNK1/JNK3 versus JNK2. The most potent compounds were 10c (11H-indeno[1,2-b]quinoxalin-11-one O-(O-ethylcarboxymethyl) oxime) and tryptanthrin-6-oxime, which had dissociation constants (Kd) for JNK1 and JNK3 of 22 and 76 nM and 150 and 275 nM, respectively. Molecular modeling suggested a mode of binding interaction at the JNK catalytic site and that the selected oxime derivatives were potentially competitive JNK inhibitors. JNK binding activity of the compounds correlated with their ability to inhibit lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) activation in human monocytic THP-1Blue cells and interleukin-6 (IL-6) production by human MonoMac-6 cells. Thus, oximes with indenoquinoxaline and tryptanthrin nuclei can serve as specific small-molecule modulators for mechanistic studies of JNK, as well as potential leads for the development of anti-inflammatory drugs.