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Discovery of 5-Hydroxy-1,4-naphthoquinone (Juglone) Derivatives as Dual Effective Agents Targeting Platelet-Cancer Interplay through Protein Disulfide Isomerase Inhibition.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2024 Mar 14; Vol. 67 (5), pp. 3626-3642. Date of Electronic Publication: 2024 Feb 21. - Publication Year :
- 2024
-
Abstract
- In this study, a series of 2- and/or 3-substituted juglone derivatives were designed and synthesized. Among them, 9 , 18 , 22 , 30 , and 31 showed stronger inhibition activity against cell surface PDI or recombinant PDI and higher inhibitory effects on U46619- and/or collagen-induced platelet aggregation than juglone. The glycosylated derivatives 18 and 22 showed improved selectivity for inhibiting the proliferation of multiple myeloma RPMI 8226 cells, and the IC <subscript>50</subscript> values reached 61 and 48 nM, respectively, in a 72 h cell viability test. In addition, 18 and 22 were able to prevent tumor cell-induced platelet aggregation and platelet-enhanced tumor cell proliferation. The molecular docking showed the amino acid residues Gln243, Phe440, and Leu443 are important for the compound-protein interaction. Our results reveal the potential of juglone derivatives to serve as novel antiplatelet and anticancer dual agents, which are available to interrupt platelet-cancer interplay through covalent binding to PDI catalytic active site.
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 67
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38381886
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.3c02107