As part of our search for natural products active against the JNK3 kinase, two novel, charged benzylisoquinolines, latifolian A (1) and latifolian B (2), were isolated from the stem bark of the Papua New Guinean vine Gnetum latifolium. The planar structures were determined through detailed 2D NMR analysis. The relative configurations were assigned after examination of the ROESY data and through detailed molecular modeling studies.
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http://dx.doi.org/10.1021/np049616i | DOI Listing |
Eur J Med Chem
January 2025
Department of Pharmacy, Institute of Pharmaceutical Science and Technology, College of Pharmacy, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan, Kyeonggi-do, 15588, Republic of Korea. Electronic address:
JNK3, a brain-specific stress-activated protein kinase, plays a critical role in Alzheimer's disease pathogenesis through phosphorylation of Tau and APP. This study aimed to develop selective JNK3 inhibitors based on a pyrazole scaffold, focusing on (E)-1-(2-aminopyrimidin-4-yl)-4-styryl-1H-pyrazole-3-carboxamide derivatives. Through systematic structural modifications and extensive SAR analysis, we identified compounds 24a and 26a as highly potent JNK3 inhibitors, with IC values of 12 and 19 nM, respectively.
View Article and Find Full Text PDFInt Immunopharmacol
December 2024
Laboratory of Neuroendocrinology, Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, India. Electronic address:
Sepsis is a life-threatening condition characterized by a widespread inflammatory response to infection, inevitably leading to multiple organ dysfunctions. Extensive research, both in vivo and in vitro, has revealed key factors contributing to sepsis, such as apoptosis, inflammation, cytokine release, oxidative stress, and systemic stress. The changes observed during sepsis-induced conditions are mainly attributed to altered signal transduction pathways, which play a critical role in cell proliferation, migration, and apoptosis.
View Article and Find Full Text PDFBioorg Chem
December 2024
Pharmaceutical Chemistry Department, Collage of Pharmaceutical Science and Drug Manufacturing, Misr University for Science and Technology, P.O. 77, 6th of October City, Giza, Egypt.
In the present work, a new series of ethyl pyrazole-containing compounds with side sulphonamide moiety was designed and synthesized. The new derivatives were divided into four groups based on the linker between the sulphonamide and pyridine ring attached to position 4 of the pyrazole ring and the substitution on the phenyl ring at position 3 of the same ring. The linker could be ethyl or propyl linkers.
View Article and Find Full Text PDFAngew Chem Int Ed Engl
December 2024
State Key Laboratory of Biotherapy and Cancer Center, Innovation Center of Nursing Research, West China Hospital, Sichuan University, No. 17, Section 3, Renmin South Road, 610041, Chengdu, China.
c-Jun N-terminal kinases (JNKs) including JNK1/2/3 are key members of mitogen-activated protein kinase family. Wherein JNK3 is specifically expressed in brain and emerges as therapeutic target, especially for neurodegenerative diseases. However, developing JNK3 selective inhibitors as chemical probes to investigate its therapeutic potential in diseases remains challenging.
View Article and Find Full Text PDFSelectivity is a primary focus in medicinal chemistry for ATP-competitive kinase inhibitors due to the highly conserved ATP binding pockets in the kinome. A decade of medicinal chemistry efforts has been carried out to develop selective inhibitors for JNKs, resulting in the identification of numerous promising scaffolds that even exhibit isoform selectivity. Thiophene-indazole is one of the scaffolds explored for isoform selectivity.
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