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.

Keywords:

• Design and synthesis
• hit compound
• anticancer
• histone deacetylases
• isoform-selective inhibitors

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was funded by the National Natural Science Foundation of Ningbo City [No. 2021J104], the Science and Technology Plan Project of Ningbo City [No. 2022S128], the Ningbo Key Science and Technology Development Program [No. 2021Z046], the National 111 Project of China [No. D16013] and the Li Dak Sum Yip Yio Chin Kenneth Li Marine Biopharmaceutical Development Fund.