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Synthesis and Biological Evaluation of Tripartin, a Putative KDM4 Natural Product Inhibitor, and 1-Dichloromethylinden-1-ol Analogues

Lookup NU author(s): Professor Akane Kawamura


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© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. The natural product tripartin has been reported to inhibit the N-methyl-lysine histone demethylase KDM4A. A synthesis of tripartin starting from 3,5-dimethoxyphenylacrylic acid was developed, and the enantiomers were separated by chiral HPLC. We observed that both tripartin enantiomers manifested an apparent increase in H3K9me3 levels when dosed in cells, as measured by western blot analysis. Thus, there is no enantiomeric discrimination toward this natural product in terms of its effects on cellular histone methylation status. Interestingly, tripartin did not inhibit isolated KDM4A–E under our assay conditions (IC50>100 μm). Tripartin analogues with a dichloromethylcarbinol group derived from the indanone scaffold were synthesized and found to be inactive against isolated recombinant KDM4 enzymes and in cell-based assays. Although the precise cellular mode of action of tripartin is unclear, our evidence suggests that it may affect histone methylation status via a mechanism other than direct inhibition of the KDM4 histone demethylases.

Publication metadata

Author(s): Guillade L, Sarno F, Tarhonskaya H, Nebbioso A, Alvarez S, Kawamura A, Schofield CJ, Altucci L, de Lera AR

Publication type: Article

Publication status: Published

Journal: ChemMedChem

Year: 2018

Volume: 13

Issue: 18

Pages: 1949-1956

Print publication date: 19/09/2018

Online publication date: 26/07/2018

Acceptance date: 19/07/2018

ISSN (print): 1860-7179

ISSN (electronic): 1860-7187

Publisher: John Wiley and Sons Ltd


DOI: 10.1002/cmdc.201800377

PubMed id: 30047603


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