Photoswitchable diazocine-based estrogen receptor agonists: stabilization of the active form inside the receptor

Ewert, J., Heintze, L., Jordà-Redondo, M., von Glasenapp, J.-S., Nonell, S., Bucher, G. , Peifer, C. and Herges, R. (2022) Photoswitchable diazocine-based estrogen receptor agonists: stabilization of the active form inside the receptor. Journal of the American Chemical Society, 144(33), pp. 15059-15071. (doi: 10.1021/jacs.2c03649) (PMID:35952371)

Abstract

Photopharmacology is an emerging approach in drug design and pharmacological therapy. Light is used to switch a pharmacophore between a biologically inactive and an active isomer with high spatiotemporal resolution at the site of illness, thus potentially avoiding side effects in neighboring healthy tissue. The most frequently used strategy to design a photoswitchable drug is to replace a suitable functional group in a known bioactive molecule with azobenzene. Our strategy is different in that the photoswitch moiety is closer to the drug’s scaffold. Docking studies reveal a very high structural similarity of natural 17β-estradiol and the E isomers of dihydroxy diazocines, but not their Z isomers, respectively. Seven dihydroxy diazocines were synthesized and subjected to a biological estrogen reporter gene assay. Four derivatives exhibit distinct estrogenic activity after irradiation with violet light, which can be shut off with green light. Most remarkably, the photogenerated, active E form of one of the active compounds isomerizes back to the inactive Z form with a half-life of merely several milliseconds in water, but nevertheless is active for more than 3 h in the presence of the estrogen receptor. The results suggest a significant local impact of the ligand–receptor complex toward back-isomerization. Thus, drugs that are active when bound but lose their activity immediately after leaving the receptor could be of great pharmacological value because they strongly increase target specificity. Moreover, the drugs are released into the environment in their inactive form. The latter argument is particularly important for drugs that act as endocrine disruptors.

• Item Type: Articles
• Additional Information: The authors are grateful for support by the Deutsche Bundesstiftung Umwelt (DBU) and the Deutsche Forschungsgemeinschaft via SFB 677.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Bucher, Dr Goetz
• Authors: Ewert, J., Heintze, L., Jordà-Redondo, M., von Glasenapp, J.-S., Nonell, S., Bucher, G., Peifer, C., and Herges, R.
• College/School: College of Science and Engineering > School of Chemistry
• Journal Name: Journal of the American Chemical Society
• Publisher: American Chemical Society
• ISSN: 0002-7863
• ISSN (Online): 1520-5126
• Published Online: 11 August 2022