109523-13-9Relevant articles and documents
Discovery, Optimization, and Evaluation of Quinazolinone Derivatives with Novel Linkers as Orally Efficacious Phosphoinositide-3-Kinase Delta Inhibitors for Treatment of Inflammatory Diseases
Liu, Kongjun,Li, Dan,Zheng, Wei,Shi, Mingsong,Chen, Yong,Tang, Minghai,Yang, Tao,Zhao, Min,Deng, Dexin,Zhang, Chufeng,Liu, Jiang,Yuan, Xue,Yang, Zhuang,Chen, Lijuan
, p. 8951 - 8970 (2021)
Guided by molecular docking, a commonly used open-chain linker was cyclized into a five-membered pyrrolidine to lock the overall conformation of the propeller-shaped molecule. Different substituents were introduced into the pyrrolidine moiety to block oxidative metabolism. Surprisingly, it was found that a small methyl substituent could be used to alleviate the oxidative metabolism of pyrrolidine while maintaining or enhancing potency, which could be described as a "magic methyl". Further optimization around the "3rd blade"of the propeller led to identification of a series of potent and selective PI3Kδinhibitors. Among them, compound 50 afforded an optimum balance of PK profiles and potency. Oral administration of 50 attenuated the arthritis severity in a dose-dependent manner in a collagen-induced arthritis model without obvious toxicity. Furthermore, 50 demonstrated excellent pharmacokinetic properties with high bioavailability, suggesting that 50 might be an acceptable candidate for treatment of inflammatory diseases.
Promotion of the collagen triple helix in a hydrophobic environment
Kubyshkin, Vladimir,Budisa, Nediljko
, p. 2502 - 2507 (2019)
In contrast to many other water-soluble peptide arrangements, the formation of a triple helix in collagen proceeds inside out: polar glycyl residues form the interior, whereas nonpolar prolyl side chains constitute the exterior. In our work, we decided to exploit this aspect of the peptide architecture in order to create hyperstable collagen mimicking peptides (CMPs). The key element of this study is the environment. Given that the peptide assembles in a nonpolar medium, the collapse of the polar peptide backbone into the triple helix should become more favorable. Following this idea, we prepared CMPs based on hydrophobic proline analogues. The synthesis was performed by a combination of liquid- and solid-phase approaches: first, hexapeptides were prepared in solution, and then these were launched into conventional Fmoc-based peptide synthesis on a solid support. The resulting peptides showed an excellent signal of the triple helix in the model nonpolar solvent (octanol) according to circular dichroism observations. In a study of a series of oligomers, we found that the minimal length of the peptides required for triple helical assembly is substantially lower compared to water-soluble CMPs. Our results suggest further explorations of the CMPs in hydrophobic media; in particular, we highlight the suggestion that collagen could be converted into a membrane protein.
Amide Iridium Complexes As Catalysts for Transfer Hydrogenation Reduction of N-sulfonylimine
Wen, Huiling,Luo, Nianhua,Zhu, Qianheng,Luo, Renshi
, p. 3850 - 3859 (2021/03/09)
Sulfonamide moieties widely exist in natural products, biologically active substance, and pharmaceuticals. Here, an efficient water-soluble amide iridium complexes-catalyzed transfer hydrogenation reduction of N-sulfonylimine is developed, which can be carried out under environmentally friendly conditions, affording a series of sulfonamide compounds in excellent yields (96-98%). In comparison with organic solvents, water is shown to be critical for a high catalytic transfer hydrogenation reduction in which the catalyst loading can be as low as 0.001 mol %. These amide iridium complexes are easy to synthesize, one structure of which was determined by single-crystal X-ray diffraction. This protocol gives an operationally simple, practical, and environmentally friendly strategy for synthesis of sulfonamide compounds.
Substituted quinazoline -4 - ketone compound as well as preparation method and application thereof
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Paragraph 0108-0112, (2021/10/20)
The invention relates to a substituted quinazoline -4 - ketone compound and a preparation method and application thereof, and belongs to the field of chemical medicines. The invention provides a compound shown I. A pharmaceutically acceptable salt, a stereoisomer or a solvate thereof. The invention further provides a preparation method and application of the compound. Biological experiments show that the compound has good inhibitory activity on PI3K. , The compound has good inhibitory activity on multiple tumor cell proliferation, wherein certain compounds exhibit better anti-proliferative activity than CAL-101 and IPI-145. The compound disclosed by the invention also has a good anti-inflammatory effect.
