Visible‐Light‐Triggered Activation of a Protein Kinase Inhibitor

Wilson, Danielle; Li, Jason W.; Branda, Neil R.

doi:10.1002/cmdc.201600632

Cited by 33 publications

(29 citation statements)

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“…On one hand, Ferreira et al . and Wilson et al . published the first promising examples, including a photoswitchable azo‐functionalized RET kinase inhibitor and a diarylethene‐based protein kinase C inhibitor.…”

Section: Introductionmentioning

confidence: 99%

“…Reversibly photoswitchable kinase inhibitors could overcome these limitations, but the development of such compounds seems to be challenging. On one hand, Ferreira et al [23] and Wilson et al [24] published the first promising examples,i ncluding ap hotoswitchable azo-functionalized RET kinase inhibitor and ad iarylethene-based protein kinase Ci nhibitor.O nt he other hand, these compounds…”

Section: Introductionmentioning

confidence: 99%

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Axitinib: A Photoswitchable Approved Tyrosine Kinase Inhibitor

et al. 2018

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The goal of photopharmacology is to develop photoswitchable enzyme modulators as tunable (pro-)drugs that can be spatially and temporally controlled by light. In this context, the tyrosine kinase inhibitor axitinib, which contains a photosensitive stilbene-like moiety that allows for E/Z isomerization, is of interest. Axitinib is an approved drug that targets the vascular endothelial growth factor receptor 2 (VEGFR2) and is licensed for second-line therapy of renal cell carcinoma. The photoinduced E/Z isomerization of axitinib has been investigated to explore if its inhibitory effect can be turned "on" and "off", as triggered by light. Under controlled light conditions, (Z)-axitinib is 43 times less active than that of the E isomer in an VEGFR2 assay. Furthermore, it was proven that kinase activity in human umbilical vein cells (HUVECs) was decreased by (E)-axitinib, but only weakly affected by (Z)-axitinib. By irradiating (Z)-axitinib in vitro with UV light (λ=385 nm), it is possible to switch it almost quantitatively into the E isomer and to completely restore the biological activity of (E)-axitinib. However, switching the biological activity off from (E)- to (Z)-axitinib was not possible in aqueous solution due to a competing irreversible [2+2]-photocycloaddition, which yielded a biologically inactive axitinib dimer.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Axitinib: A Photoswitchable Approved Tyrosine Kinase Inhibitor

et al. 2018

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“…For each experiment aD MSO blank was performed simultaneously, and data were corrected. For compounds 19, 21, 35 and 41 pre-incubation (30 s) and the following CRC of histamine was implemented by permanent irradiation at 365 nm (19 and 21), 420 nm (35)o r4 00 nm (41). Ap re-incubation and the accompanying light exposure of 15, 10, 5a nd 3min had an influence at the tissue's contractility,r esulting in ad epression of the CRCs of histamine.…”

Section: Organ-pharmacological Testingmentioning

confidence: 99%

“…Additional benefits, besides their large geometrical change, include reversibility of 10 5 to 10 6 cycles without detectable photodegradation or loss of responsiveness, synthetic accessibility via Mills reaction, oxidative/reductive coupling or azo coupling, and tunability of their photochromic properties . Furthermore, azobenzene‐based photoresponsive systems have already been successfully applied in several biological systems . Recently, the research groups of Wijtmans and Leurs reported the use of a bidirectional photoswitchable antagonist toolbox for the H 3 R, a GPCR, based on azobenzene …”

Section: Introductionmentioning

confidence: 99%

“…[33][34][35][36] Furthermore, azobenzene-based photoresponsive systems have already been successfully appliedi ns everal biological systems. [37][38][39][40][41] Recently,t he research groups of Wijtmans and Leurs reported the use of ab idirectional photoswitchable antagonist toolbox for the H 3 R, aG PCR, based on azobenzene. [16] We designed ap hotochromic antagonist for the H 1 Rb ased on azobenzene as the photochromic scaffold.…”

Section: Introductionmentioning

confidence: 99%

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Light‐Switchable Antagonists for the Histamine H₁ Receptor at the Isolated Guinea Pig Ileum

2019

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The histamine H1 G protein‐coupled receptor (GPCR) plays an important role in allergy and inflammation. Existing drugs that address the H1 receptor differ in their chemical structure, pharmacology, and side effects. Light‐controllable spatial and temporal activity regulation of photochromic H1 ligands may contribute to a better mechanistic understanding and the development of improved correlations between ligand structure and pharmacologic effects. We report photochromic H1 receptor ligands, which were investigated in an organ‐pharmacological assay. Initially, five photochromic azobenzene derivatives of reported dual H1–H4 receptor antagonists were designed, synthesized, photochemically characterized, and organ‐pharmacologically tested on the isolated guinea pig ileum. Among them, one compound [trans‐19: (Z)‐1‐(4‐chlorophenyl)‐1‐(4‐methylpiperazin‐1‐yl)‐N‐(4‐((E)‐phenyldiazenyl)phenyl)methanimine] retained the antagonistic activity of its non‐photochromic lead, and trans–cis isomerization by irradiation induced a fourfold difference in the pharmacological response. Further structural optimization resulted in two bathochromically shifted derivatives of 19 [NO2‐substituted 35 {(Z)‐1‐(4‐chlorophenyl)‐1‐(4‐methylpiperazin‐1‐yl)‐N‐(4‐((E)‐(4‐nitrophenyl)diazenyl)phenyl)methanimine} and SO3−‐substituted 41 {4‐((E)‐(4‐(((Z)‐(4‐chlorophenyl)(4‐methylpiperazin‐1‐yl)methylene)amino)phenyl)diazenyl)benzenesulfonate}], which do not require the use of UV light for photoisomerization and which also have improved solubility and show reduced tissue impairment. The trans isomers of both compounds showed a remarkable increase in antagonistic activity relative to their lead trans‐19; furthermore, a 46‐fold difference in activity on the isolated guinea pig ileum was observed between trans‐ and cis‐35.

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Future‐Oriented Advanced Diarylethene Photoswitches: From Molecular Design to Spontaneous Assembly Systems

et al. 2022

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cycloreversion of DAE under light irradiation produces many exciting functional effects, such as changes in photophysical and photochemical properties, [12] changes in the shape or mechanical properties of the solid, [13] electrical conductivity, [7b,14] and the generation of reactive oxygen species (ROS). [15] This type of photochromic compound can be considered a stilbene derivative. At this time, the most widely known and systematically studied DAE derivative structure contains two aryl groups and a benzene ring (usually two identical or different thiophene units with low aromatic stabilization energy [16] ) and a five-membered ring of perfluorocyclopentene and cyclopentene units [17] where the ethene bridge is located, which significantly improve photochromism. [18] In essence, the DAE photoisomerization process is a reversible electrocyclic reaction of the central 6π-electron systems. [2] Under light irradiation, DAE can rapidly and reversibly transform between its open and closed forms, and that transformation is accompanied by a color change caused by a change in the π-conjugation distribution. [2] The important thing is that the colorless opened-and colored closed-ring isomers are both thermally stable; that is, cyclization and cycloreversion do not proceed spontaneously in the dark; they need to be driven by external light irradiation at specific wavelengths. [2,19] Compared with classic lightresponsive molecules such as azobenzene, [20] the light intensity required to drive the isomerization of DAE is relatively low. Moreover, even after multiple cycles, the photochromic performance does not show significant fatigue in either the solution or solid state. [2,18b,21] DAE research to this point can be roughly divided into three stages in chronological order: early exploration of DAE's molecular structure and theory, nearly two decades of purpose-oriented molecular structure modification research, and about ten years of research into practical applications of DAE in assembly systems. Research before about 2000 focused mainly on developing more abundant DAE-derivative structures and advancing the systematic understanding of DAE's physical and chemical properties and switching performance. To regulate its switching performance and give it new functionality, many strategies for modifying the ethene bridge and aryl groups of DAE have been proposed. [22] In the first two research stages, the mechanisms and structural modification of DAE isomerization were thoroughly and systematically explored, and countless important Diarylethene (DAE) photoswitch is a new and promising family of photochromic molecules and has shown superior performance as a smart trigger in stimulus-responsive materials. During the past few decades, the DAE family has achieved a leap from simple molecules to functional molecules and developed toward validity as a universal switching building block. In recent years, the introduction of DAE into an assembly system has been an attractive strategy that enables the photochromic behavior of the b...

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Visible‐Light‐Triggered Activation of a Protein Kinase Inhibitor

Cited by 33 publications

References 50 publications

Axitinib: A Photoswitchable Approved Tyrosine Kinase Inhibitor

Axitinib: A Photoswitchable Approved Tyrosine Kinase Inhibitor

Light‐Switchable Antagonists for the Histamine H₁ Receptor at the Isolated Guinea Pig Ileum

Future‐Oriented Advanced Diarylethene Photoswitches: From Molecular Design to Spontaneous Assembly Systems

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Visible‐Light‐Triggered Activation of a Protein Kinase Inhibitor

Cited by 33 publications

References 50 publications

Axitinib: A Photoswitchable Approved Tyrosine Kinase Inhibitor

Axitinib: A Photoswitchable Approved Tyrosine Kinase Inhibitor

Light‐Switchable Antagonists for the Histamine H1 Receptor at the Isolated Guinea Pig Ileum

Future‐Oriented Advanced Diarylethene Photoswitches: From Molecular Design to Spontaneous Assembly Systems

Contact Info

Product

Resources

About

Light‐Switchable Antagonists for the Histamine H₁ Receptor at the Isolated Guinea Pig Ileum