Reductive stability evaluation of 6-azopurine photoswitches for the regulation of CKI alpha activity and circadian rhythms

Dusan Kolarski, Akiko Sugiyama, Theo Rodat, Albert Schulte, Christian Peifer, Kenichiro Itami, Tsuyoshi Hirota, Ben L. Feringa, Wiktor Szymanski*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

8 Citaten (Scopus)
13 Downloads (Pure)

Samenvatting

Photopharmacology develops bioactive compounds whose pharmacological potency can be regulated by light. The concept relies on the introduction of molecular photoswitches, such as azobenzenes, into the structure of bioactive compounds, such as known enzyme inhibitors. Until now, the development of photocontrolled protein kinase inhibitors proved to be challenging for photopharmacology. Here, we describe a new class of heterocyclic azobenzenes based on the longdaysin scaffold, which were designed to photo-modulate the activity of casein kinase I alpha (CKI alpha) in the context of photo-regulation of circadian rhythms. Evaluation of a set of photoswitchable longdaysin derivatives allowed for better insight into the relationship between substituents and thermal stability of the cis-isomer. Furthermore, our studies on the chemical stability of the azo group in this type of heterocyclic azobenzenes showed that they undergo a fast reduction to the corresponding hydrazines in the presence of different reducing agents. Finally, we attempted light-dependent modulation of CKI alpha activity together with the accompanying modulation of cellular circadian rhythms in which CKI alpha is directly involved. Detailed structure-activity relationship (SAR) analysis revealed a new potent reduced azopurine with a circadian period lengthening effect more pronounced than that of its parent molecule, longdaysin. Altogether, the results presented here highlight the challenges in the development of light-controlled kinase inhibitors for the photomodulation of circadian rhythms and reveal key stability issues for using the emerging class of heteroaryl azobenzenes in biological applications.

Originele taal-2English
Pagina's (van-tot)2312-2321
Aantal pagina's10
TijdschriftOrganic & Biomolecular Chemistry
Volume19
Nummer van het tijdschrift10
DOI's
StatusPublished - 14-mrt-2021

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