A toolbox of molecular photoswitches to modulate the CXCR3 chemokine receptor with light

Xavier Gómez-Santacana; Sabrina M. De Munnik; Tamara A.M. Mocking; Niels J. Hauwert; Shanliang Sun; Prashanna Vijayachandran; Iwan J.P. De Esch; Henry F. Vischer; Maikel Wijtmans; Rob Leurs

doi:10.3762/bjoc.15.244

A toolbox of molecular photoswitches to modulate the CXCR3 chemokine receptor with light

Xavier Gómez-Santacana
, Sabrina M. De Munnik
, Tamara A.M. Mocking
, Niels J. Hauwert
, Shanliang Sun
, Prashanna Vijayachandran
, Iwan J.P. De Esch
, Henry F. Vischer
, Maikel Wijtmans^*
, Rob Leurs

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

We report a detailed structure–activity relationship for the scaffold of VUF16216, a compound we have previously communicated as a small-molecule efficacy photoswitch for the peptidergic chemokine GPCR CXCR3. A series of photoswitchable azobenzene ligands was prepared through various synthetic strategies and multistep syntheses. Photochemical and pharmacological properties were used to guide the design iterations. Investigations of positional and substituent effects reveal that halogen substituents on the ortho-position of the outer ring are preferred for conferring partial agonism on the cis form of the ligands. This effect could be expanded by an electron-donating group on the para-position of the central ring. A variety of efficacy differences between the trans and cis forms emerges from these compounds. Tool compounds VUF15888 (4d) and VUF16620 (6e) represent more subtle efficacy switches, while VUF16216 (6f) displays the largest efficacy switch, from antagonism to full agonism. The compound class disclosed here can aid in new photopharmacology studies of CXCR3 signaling.

Original language	English
Pages (from-to)	2509-2523
Number of pages	15
Journal	Beilstein Journal of Organic Chemistry
Volume	15
DOIs	https://doi.org/10.3762/bjoc.15.244
Publication status	Published - 23 Oct 2019

Funding

All authors acknowledge the Netherlands Organization for Scientific Research for financial support (TOPPUNT, “7 ways to 7TMR modulation (7-to-7)”, 718.014.002). We thank Danny Scholten, Chris de Graaf, and Luc Roumen for helpful discussions, Hans Custers for recording HRMS spectra and Mounir Andaloussi for providing key building block 7.

Funders	Funder number
Netherlands Organization for Scientific Research
???publication-publication-funding-organisation-not-added???	718.014.002

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Azo compounds
Chemokine receptor
Efficacy photoswitching
G protein-coupled receptors
Photopharmacology

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10.3762/bjoc.15.244

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title = "A toolbox of molecular photoswitches to modulate the CXCR3 chemokine receptor with light",

abstract = "We report a detailed structure–activity relationship for the scaffold of VUF16216, a compound we have previously communicated as a small-molecule efficacy photoswitch for the peptidergic chemokine GPCR CXCR3. A series of photoswitchable azobenzene ligands was prepared through various synthetic strategies and multistep syntheses. Photochemical and pharmacological properties were used to guide the design iterations. Investigations of positional and substituent effects reveal that halogen substituents on the ortho-position of the outer ring are preferred for conferring partial agonism on the cis form of the ligands. This effect could be expanded by an electron-donating group on the para-position of the central ring. A variety of efficacy differences between the trans and cis forms emerges from these compounds. Tool compounds VUF15888 (4d) and VUF16620 (6e) represent more subtle efficacy switches, while VUF16216 (6f) displays the largest efficacy switch, from antagonism to full agonism. The compound class disclosed here can aid in new photopharmacology studies of CXCR3 signaling.",

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AU - Gómez-Santacana, Xavier

AU - De Munnik, Sabrina M.

AU - Mocking, Tamara A.M.

AU - Hauwert, Niels J.

AU - Sun, Shanliang

AU - Vijayachandran, Prashanna

AU - De Esch, Iwan J.P.

AU - Vischer, Henry F.

AU - Wijtmans, Maikel

AU - Leurs, Rob

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N2 - We report a detailed structure–activity relationship for the scaffold of VUF16216, a compound we have previously communicated as a small-molecule efficacy photoswitch for the peptidergic chemokine GPCR CXCR3. A series of photoswitchable azobenzene ligands was prepared through various synthetic strategies and multistep syntheses. Photochemical and pharmacological properties were used to guide the design iterations. Investigations of positional and substituent effects reveal that halogen substituents on the ortho-position of the outer ring are preferred for conferring partial agonism on the cis form of the ligands. This effect could be expanded by an electron-donating group on the para-position of the central ring. A variety of efficacy differences between the trans and cis forms emerges from these compounds. Tool compounds VUF15888 (4d) and VUF16620 (6e) represent more subtle efficacy switches, while VUF16216 (6f) displays the largest efficacy switch, from antagonism to full agonism. The compound class disclosed here can aid in new photopharmacology studies of CXCR3 signaling.

AB - We report a detailed structure–activity relationship for the scaffold of VUF16216, a compound we have previously communicated as a small-molecule efficacy photoswitch for the peptidergic chemokine GPCR CXCR3. A series of photoswitchable azobenzene ligands was prepared through various synthetic strategies and multistep syntheses. Photochemical and pharmacological properties were used to guide the design iterations. Investigations of positional and substituent effects reveal that halogen substituents on the ortho-position of the outer ring are preferred for conferring partial agonism on the cis form of the ligands. This effect could be expanded by an electron-donating group on the para-position of the central ring. A variety of efficacy differences between the trans and cis forms emerges from these compounds. Tool compounds VUF15888 (4d) and VUF16620 (6e) represent more subtle efficacy switches, while VUF16216 (6f) displays the largest efficacy switch, from antagonism to full agonism. The compound class disclosed here can aid in new photopharmacology studies of CXCR3 signaling.

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KW - G protein-coupled receptors

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A toolbox of molecular photoswitches to modulate the CXCR3 chemokine receptor with light

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UN SDGs

Keywords

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