Bioorg Med Chem Lett
The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), 325 Guohe Road, Shanghai 200433, PR China. Electronic address:
Published: September 2024
Aberrant activation of the JAK-STAT pathway is evident in various human diseases including cancers. Proteolysis targeting chimeras (PROTACs) provide an attractive strategy for developing novel JAK-targeting drugs. Herein, a series of CRBN-directed JAK-targeting PROTACs were designed and synthesized utilizing a JAK1/JAK2 dual inhibitor-momelotinib as the warhead. The most promising compound 10c exhibited both good enzymatic potency and cellular antiproliferative effects. Western blot analysis revealed that compound 10c effectively and selectively degraded JAK1 in a proteasome-dependent manner (DC = 214 nM). Moreover, PROTAC 10c significantly suppressed JAK1 and its key downstream signaling. Together, compound 10c may serve as a novel lead compound for antitumor drug discovery.
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http://dx.doi.org/10.1016/j.bmcl.2024.129838 | DOI Listing |
Anticancer Agents Med Chem
January 2025
Department of Chemistry, Faculty of Science, Cairo University, A. R, Egypt.
Background: Xanthene derivatives are a notable class of heterocyclic compounds widely studied for their significant biological impact. These molecules, found in both natural and synthetic forms, have attracted substantial scientific interest due to their broad spectrum of biological activities. The xanthene nucleus, in particular, is associated with a range of potential pharmaceutical properties, including antibacterial, antiviral, antiinflammatory, anticancer, and antioxidant effects.
View Article and Find Full Text PDFJ Med Chem
January 2025
Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
The main protease (M) of SARS-CoV-2 is a key drug target for the development of antiviral therapeutics. Here, we designed and synthesized a series of small-molecule peptidomimetics with various cysteine-reactive electrophiles. Several compounds were identified as potent SARS-CoV-2 M inhibitors, including compounds (IC = 0.
View Article and Find Full Text PDFChem Biodivers
January 2025
Taibah University, Chemistry, Um alqara, Alula, SAUDI ARABIA.
In the current study, new pyranopyrazole analogues (9a-d and 10a-d) were synthesized through a one-pot condensation reaction of 2-arylacetohydrazide. The inhibitory abilities were investigated against the XO enzyme through experimental and molecular docking analyses. The synthesis studies were based on ultrasound-mediated condensation reactions of four-component systems containing 2-arylacetohydrazide, ethyl acetoacetate, indoline-2,3-dione, and ethyl 2-cyanoacetate/malononitrile in various solvents and catalysts to yield pyranopyrazole analogues (9a-d and 10a-d) in a short reaction time and remarkably favorable yields ranging from 79-92%.
View Article and Find Full Text PDFJ Nat Prod
January 2025
Department of Natural Products, National Institute of Pharmaceutical Education and Research-Ahmedabad (NIPER-A), An Institute of National Importance, Government of India, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Opp. Airforce Station, Palaj, Gandhinagar 382355, Gujarat, India.
Inspired by our previous efforts in the semisynthetic modification of naturally occurring pyranoacridones, we report the targeted design and semisynthesis of dual inhibitors of HDAC and topoisomerase II α (Topo II α) derived from des--methylacronycine () and noracronycine () pyranoacridone alkaloids. Designed from the clinically approved SAHA, the cytotoxic pyranoacridone nuclei from the alkaloids served as the capping group, while a hydroxamic acid moiety functioned as the zinc-binding group. Out of 16 compounds evaluated in an cytotoxicity assay, KT32 () with noracronycine () as the capping group and five-carbon linker hydroxamic acid side chains showed good cytotoxic activity with IC values of 1.
View Article and Find Full Text PDFSci Rep
December 2024
Faculty of Science, Botany Department, Mansoura University, Mansoura, 35516, Egypt.
In the present study, extracellular cell-free filtrate (CFF) of fungal Fusarium oxysporum f. sp. cucumerinum (FOC) species, was utilized to biosynthesize zinc oxide /zinc sulfide (ZnO/ZnS) nanocomposite.
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