Light-switchable diazocines as potential inhibitors of testosterone-synthesizing 17β-hydroxysteroid dehydrogenase 3

• Published in: Chemico-biological interactions 2024-02, Vol.390, p.110872-110872, Article 110872
• Main Authors: Wages, F., Brandt, T., Martin, H.-J., Herges, R., Maser, E.
• Format: Article
• Language: English
• Subjects: 17β-hydroxysteroid dehydrogenase 3; Enzyme inhibition; Irradiation; N-acetyl diazocine; Photopharmacology; Photoswitch; Prostate cancer
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2024.110872

In patients with prostate carcinoma as well as in some other cancer types, the reduction of testosterone levels is desired because the hormone stimulates cancer cell growth. One molecular target for this goal is the inhibition of 17β-hydroxysteroid dehydrogenase type 3 (17βHSD3), which produces testosterone from its direct precursor androstenedione. Recent research in this field is trying to harness photopharmacological properties of certain compounds so that the inhibitory effect could be turned on and off by irradiation. Seven new light-switchable diazocines were investigated with regard to their inhibition of 17βHSD3. For this purpose, transfected HEK-293 cells and isolated microsomes were treated with the substrate and the potential inhibitors with and without irradiation for an incubation period of 3 or 5 h. The amount of generated testosterone was measured by UHPLC and compared between samples and control as well as between irradiated and non-irradiated samples. There was no significant difference between samples with and without irradiation. However, four of the seven diazocines led to a significantly lower testosterone production both in cell and in microsome assays. In some of the irradiated samples, a partial destruction of the diazocines was observed, indicated by an additional UHPLC peak. However, the influence on the inhibition is negligible, because the majority of the substance remained intact. In conclusion, new inhibitors of 17βHSD3 have been found, but so far without the feature of a light switch, since the configurational alteration of the diazocines by irradiation did not lead to a change in bioactivity. Further modification might help to find a light-switching molecule that inhibits only in one configuration. •Testosterone synthesis is aimed to be decreased by 17βHSD3 inhibition.•Four new photoswitchable diazocines were found to inhibit 17βHSD3.•Inhibition of irradiated and non-irradiated diazocines does not differ significantly.•Reduction may contribute to the limited inhibition of photoswitched diazocines.