Photoswitchable Azo- and Diazocine-Functionalized Derivatives of the VEGFR-2 Inhibitor Axitinib

Abstract

In this study, we aimed at the application of the concept of photopharmacology to the approved vascular endothelial growth factor receptor (VEGFR)-2 kinase inhibitor axitinib. In a previous study, we found out that the photoisomerization of axitinib’s stilbene-like double bond is unidirectional in aqueous solution due to a competing irreversible [2+2]-cycloaddition. Therefore, we next set out to azologize axitinib by means of incorporating azobenzenes as well as diazocine moieties as photoresponsive elements. Conceptually, diazocines (bridged azobenzenes) show favorable photoswitching properties compared to standard azobenzenes because the thermodynamically stable Z-isomer usually is bioinactive, and back isomerization from the bioactive E-isomer occurs thermally. Here, we report on the development of different sulfur–diazocines and carbon–diazocines attached to the axitinib pharmacophore that allow switching the VEGFR-2 activity reversibly. For the best sulfur–diazocine, we could verify in a VEGFR-2 kinase assay that the Z-isomer is biologically inactive (IC50 >> 10,000 nM), while significant VEGFR-2 inhibition can be observed after irradiation with blue light (405 nm), resulting in an IC50 value of 214 nM. In summary, we could successfully develop reversibly photoswitchable kinase inhibitors that exhibit more than 40-fold differences in biological activities upon irradiation. Moreover, we demonstrate the potential advantage of diazocine photoswitches over standard azobenzenes.

Substituted nitrogen-bridged diazocines

“…Our previously published NAc-bridged diazocine 10c ( Scheme 1 , Table 1 ) exhibits both properties [ 15 ]. This is in stark contrast to the CH 2 –CH 2 and S–CH 2 -bridged diazocines and the majority of azobenzenes [ 9 , 16 – 20 ]. Spurred by the promising properties of CH 2 –NR-bridged diazocines (triazocines), we now explored this class of photoswitches and developed synthetic access to these photochromes ( Figure 1 ).…”

“…Parent diazocine (CH 2 –CH 2 -bridged) exhibits well-separated n– π* transitions, which allow excellent photoconversion between the Z and E configurations (( Z → E ) 385 nm = 92%, ( E → Z ) 525 nm > 99% in n -hexane) with light in the visible region [ 1 ]. Moreover, the Z -boat configuration is the thermodynamically stable isomer [ 2 – 9 ]. The latter property (i.e., the inverted stability compared to azobenzenes) makes them promising candidates for applications in photopharmacology.…”

Active Ester Functionalized Azobenzenes as Versatile Building Blocks

“…Photoswitchable molecules add photoresponsiveness to diverse materials such as polymers [ 1 , 2 , 3 , 4 , 5 , 6 ], dendrimers [ 7 , 8 ] or biomolecules [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. By precise adjustment of the synthetic strategy the switch can be incorporated into the target material and its switching properties can be utilized.…”

Substituted Nitrogen-Bridged Diazocines

“…1 Moreover, the Z-boat configuration is the thermodynamically stable isomer. 2,3,4,5,6,7,8,9 The latter property (inverted stability compared to azobenzenes) makes them promising candidates for applications in photopharmacology. In the majority of azobenzene-based photopharmacophores, the bent Z configuration is biologically inactive.…”

“…15 This is in stark contrast to the CH2-CH2, and S-CH2 bridged diazocines and the majority of azobenzenes. 9,16,17,18,19,20 Spurred by the promising properties of CH2-NR bridged 3 diazocines (triazocines), we now explore this class of photoswitches and develop synthetic access to these photochromes.…”