Issue 18, 2022

Synthesis of potent and selective HDAC6 inhibitors led to unexpected opening of a quinazoline ring

Abstract

Histone deacetylase (HDAC) inhibitors are highly involved in the regulation of many pharmacological responses, which results in anti-inflammatory and anti-cancer effects. In the present work, chemoinformatic analyses were performed to obtain two potent and selective aminotriazoloquinazoline-based HDAC6 inhibitors. We unexpectedly obtained an aminotriazole from a water-driven ring opening of the triazoloquinazoline scaffold. Both compounds were evaluated as HDAC6 inhibitors, resulting in subnanomolar inhibitory activity and high selectivity with respect to class I HDAC1 and HDAC8. Importantly, the compounds were about 3- and 15-fold more potent compared to the reference compound trichostatin A. Additionally, the predicted binding modes were investigated with docking. Considering that the aminotriazole scaffold has never been embedded into the chemical structure of HDAC6 inhibitors, the present study suggests that both the aminotriazoloquinazoline and aminotriazole classes of compounds could be excellent starting points for further optimization of potential anticancer compounds, introducing such novel groups into a relevant and new area of investigation.

Graphical abstract: Synthesis of potent and selective HDAC6 inhibitors led to unexpected opening of a quinazoline ring

Supplementary files

Article information

Article type
Paper
Submitted
17 Mar 2022
Accepted
06 Apr 2022
First published
13 Apr 2022
This article is Open Access
Creative Commons BY license

RSC Adv., 2022,12, 11548-11556

Synthesis of potent and selective HDAC6 inhibitors led to unexpected opening of a quinazoline ring

D. Moi, A. Citarella, D. Bonanni, L. Pinzi, D. Passarella, A. Silvani, C. Giannini and G. Rastelli, RSC Adv., 2022, 12, 11548 DOI: 10.1039/D2RA01753A

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