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

11 March 2024, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


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 an hemithioindigo moiety, which display a light-dependent effect on both HDAC inhibition and cancer cell viability.



Supplementary materials

Experimental methods and Supplementary Figures
- Synthetic procedures - Photochemical procedures - Biology procedures - Supplementary Figures - HPLC traces of final compounds


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