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Discovery of novel polysubstituted N-alkyl acridone analogues as histone deacetylase isoform-selective inhibitors for cancer therapy.

ABSTRACT: Pan-histone deacetylase (HDAC) inhibitors often have some toxic side effects. In this study, three series of novel polysubstituted N-alkyl acridone analogous were designed and synthesised as HDAC isoform-selective inhibitors. Among them, 11b and 11c exhibited selective inhibition of HDAC1, HDAC3, and HDAC10, with IC₅₀ values ranging from 87 nM to 418 nM. However, these compounds showed no inhibitory effect against HDAC6 and HDAC8. Moreover, 11b and 11c displayed potent antiproliferative activity against leukaemia HL-60 cells and colon cancer HCT-116 cells, with IC₅₀ values ranging from 0.56 μM to 4.21 μM. Molecular docking and energy scoring functions further analysed the differences in the binding modes of 11c with HDAC1/6. In vitro anticancer studies revealed that the hit compounds 11b and 11c effectively induced histone H3 acetylation, S-phase cell cycle arrest, and apoptosis in HL-60 cells in a concentration-dependent manner.

SUBMITTER: Wang Z

PROVIDER: S-EPMC10165928 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Discovery of novel polysubstituted N-alkyl acridone analogues as histone deacetylase isoform-selective inhibitors for cancer therapy.

Wang Ze Z Zhao Li L Zhang Bo B Feng Jiahe J Wang Yule Y Zhang Bin B Jin Haixiao H Ding Lijian L Wang Ning N He Shan S

Journal of enzyme inhibition and medicinal chemistry 20231201 1

Pan-histone deacetylase (HDAC) inhibitors often have some toxic side effects. In this study, three series of novel polysubstituted N-alkyl acridone analogous were designed and synthesised as HDAC isoform-selective inhibitors. Among them, 11b and 11c exhibited selective inhibition of HDAC1, HDAC3, and HDAC10, with IC50 values ranging from 87 nM to 418 nM. However, these compounds showed no inhibitory effect against HDAC6 and HDAC8. Moreover, 11b and 11c</ ...[more]

PMID: 37144599

Dataset Information

Discovery of novel polysubstituted N-alkyl acridone analogues as histone deacetylase isoform-selective inhibitors for cancer therapy.

Publications

Discovery of novel polysubstituted <i>N</i>-alkyl acridone analogues as histone deacetylase isoform-selective inhibitors for cancer therapy.

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