Hemithioindigo-based histone deacetylase inhibitors induce a light-dependent anticancer effect

• Published in: European journal of medicinal chemistry Vol. 279; p. 116846
• Main Authors: Josa-Culleré, Laia, Aira Rodríguez, Carla, Llebaria, Amadeu
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 05-12-2024
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116846

Photoswitchable molecules exhibit light-dependent biological activity which allow us to control the therapeutic effect of drugs with high precision. Such molecules could solve some of the limitations of anticancer drugs by providing a localised effect in the tumour. Histone deacetylase inhibitors (HDACis) constitute a promising drug class for oncology whose application is often limited by a lack of selectivity. Herein, we developed photoswitchable HDACis based on a hemithioindigo scaffold. We established synthetic routes to access them and determined the optimal conditions for isomerisation and their thermal stability. We then optimised their enzyme activity through three rounds of re-design to identify examples that are up to 6-fold more active under illumination than in the dark. We also confirmed that our best derivative reduces the viability of HeLa cells only under illumination. All in all, we disclose a series of derivatives containing a hemithioindigo moiety, which display a light-dependent effect on both HDAC inhibition and cancer cell viability.
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•A series of hemithioindigo derivatives were synthesised and photochemically characterised.•The activity of the compounds was optimised to achieve light-dependent inhibition of HDAC1.•Compound 66a was more active under illumination than in the dark in HDAC1 inhibition assays in a reversible manner.•Compound 66a decreased HeLa cell viability under illumination but not in the dark.