Photochromic Dopamine Receptor Ligands Based on Dithienylethenes and Fulgides

Lachmann, Daniel; Studte, Carolin; Männel, Barbara; Hübner, Harald; Gmeiner, Peter; König, Burkhard

doi:10.1002/chem.201702147

Cited by 43 publications

(46 citation statements)

References 67 publications

(73 reference statements)

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“…The repertoire of molecular photoswitches is large, and many have been reported as photoswitch concepts (especially for cell‐free in vitro studies); for example, photoswitch concepts depending on fulgides, stilbenes, and diarylethenes have been reported for an interesting range of biological targets. However, azobenzenes remain essentially the only photoswitch to have been validated as a photopharmacological scaffold through multiple in cellulo to in vivo biological applications.…”

Section: Introductionmentioning

confidence: 99%

Hemithioindigos for Cellular Photopharmacology: Desymmetrised Molecular Switch Scaffolds Enabling Design Control over the Isomer‐Dependency of Potent Antimitotic Bioactivity

et al. 2019

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Druglike small molecules with photoswitchable bioactivity—photopharmaceuticals—allow biologists to perform studies with exquisitely precise and reversible, spatial and temporal control over critical biological systems inaccessible to genetic manipulation. The photoresponsive pharmacophores disclosed have been almost exclusively azobenzenes, which has limited the structural and substituent scope of photopharmacology. More detrimentally, for azobenzene reagents, it is not researchers’ needs for adapted experimental tools, but rather protein binding site sterics, that typically force whether the trans (dark) or cis (lit) isomer is the more bioactive. We now present the rational design of HOTubs, the first hemithioindigo‐based pharmacophores enabling photoswitchable control over endogenous biological activity in cellulo. HOTubs optically control microtubule depolymerisation and cell death in unmodified mammalian cells. Notably, we show how the asymmetry of hemithioindigos allows a priori design of either Z‐ or E‐ (dark‐ or lit)‐toxic antimitotics, whereas the corresponding azobenzenes are exclusively lit‐toxic. We thus demonstrate that hemithioindigos enable an important expansion of the substituent and design scope of photopharmacological interventions for biological systems.

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Section: Introductionmentioning

confidence: 99%

Hemithioindigos for Cellular Photopharmacology: Desymmetrised Molecular Switch Scaffolds Enabling Design Control over the Isomer‐Dependency of Potent Antimitotic Bioactivity

et al. 2019

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“…(b) Saponification of 6 forming the diacid E ‐ 7 . (c) Anhydride formation of E ‐ 7 (d) Imide formation of fulgide E ‐ 8 and amine 9 …”

Section: Chemical Investigations Of Fulgimidesmentioning

confidence: 99%

“…In more recent publications, fulgimides have been utilized as an alternative to most diarylethenes (except for hexafluoro‐diarylethenes) due to their more desirable photophysical properties. The limitations of diarylethenes became evident when cyclopentene‐dithienylethene derivatives displayed degradation after only a few cycles of isomerization, while dithienylmaleimides were unable to switch reversibly in aqueous buffer solutions , , …”

Section: Fulgimides As Photoswitches In Biological Investigationsmentioning

confidence: 99%

“…Other classes that have been reported for such purposes include spiropyrans, hemithioindigos,, donor‐acceptor Stenhouse adducts (DASAs) and fulgides , . The reported development of these photoswitches has successfully demonstrated the biological value of such tool compounds, however, limitations of photodegradation, incomplete photoconversion and poor thermal stability have established the need for improvement , , , . Fulgimides are imide derivatives of fulgides that have mainly been used in optical data storage, molecular computing and photomechanical materials .…”

Section: Introductionmentioning

confidence: 99%

“…Fulgimides are imide derivatives of fulgides that have mainly been used in optical data storage, molecular computing and photomechanical materials . The use of fulgimides for biological investigations has not been greatly explored despite the advantageous photophysical properties of this photoswitch , , . This minireview summarizes the chemical properties of fulgimides, as well as their application in biological investigations over the last 30 years.…”

Section: Introductionmentioning

confidence: 99%

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Fulgimides as Light‐Activated Tools in Biological Investigations

2019

Self Cite

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With high spatiotemporal control, the conformation, rigidity and electronics of photoresponsive bioactive molecules can be altered. This, in turn, allows for control over the biological properties of these molecules. Incorporation of a photoswitchable moiety into a number of reported inhibitors, ligands and modulators has demonstrated the ability to modulate enzyme, receptor and ion channel responses using light. To date, the major classes of photoswitches explored in biological applications have been the azobenzenes and diarylethenes. Even though the use of these photoswitches has established the value of photoresponsive molecules as biological tools, several limitations have become apparent. Fulgimides represent a promising class of photoswitches that are not widely used for such biological purposes. Their properties are similar to that of diarylethenes, as their photochromism is based on a 6π‐electrocyclic rearrangement, however, fulgimides have the added advantage of thermal stability for both isomers. Fulgimides exhibit high photostationary states and fatigue resistance, with the ability to switch in aqueous buffer solutions. In this minireview, these advantageous photophysical properties will be discussed, as well as the use of fulgimides in biological investigations.

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The First Photochromic Affinity Switch for the Human Cannabinoid Receptor 2

Dolles

Straßer

Wittmann

et al. 2018

Advanced Therapeutics

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The hCB 2 R plays an important in the immune system and is centrally expressed in microglia. The hCB 2 R activated by agonists hold great therapeutic potential, e.g., in neuroinflammation. It is currently not yet elucidated how pathophysiological processes are mediated by the hCB 2 R. Here, photochromic affinity switches based on a drugable benzimidazole core through azologization and computational studies are developed. Structure-activity relationships (SARs) lead to compounds with high selectivity over hCB 1 R that can be reversibly switched to a higher affinity cis-form proved on the receptor level by radioligand binding studies and translating into an affinity change in a functional GTPγ S assay. cAMP ELISA and the change in expression level of two genes regulated by CREB proves that the compounds act as partial agonists.agonist SR141716A (rimonabant) had been approved as a drug for obesity in European countries, albeit its putative risk of psychiatric problems led to its suspension from the market in 2008. Far less is known about the hCB 2 R and its role in the healthy, but especially in the diseased human body. It was first recognized as the "peripheral" CBR, [2] since hCB 2 Rs are localized in the immune system and modulate immune cell migration and cytokine release. [3] More recently, it was shown that the hCB 2 R is located in the central nervous system also, mainly expressed in microglial cells.Pronounced overexpression of CB 2 R and fatty acid amide hydrolase is observed in neuroinflammatory processes in the brain and specifically in microglia cells that surround β-amyloid plaques. [4] The expression level correlates well with Aβ 42 -level and plaque formation, although not directly with cognitive status, indicating that pathogenic processes lead to hCB 2 R overexpression. [5] Due to the expression of hCB 2 R in activated microglia and the possibility of reduction of cell activation by hCB 2 R agonists, therapeutic application of such compounds is promising. It was shown in several in vitro-assays that hCB 2 R agonists and partial agonists reduce both the number of activated microglia cells surrounding Aβ plaques and the level of pro-inflammatory cytokines. It is currently not yet elucidated how exactly these effects are mediated by the hCB 2 R, in which sequence (patho)physiologic activation takes place and which time-scale is underlying these processes. [6] Both hCBR subtypes are activated to the same extent by endocannabinoids and classical phytocannabinoids like 9 -THC, [7] which also activates GPR18, GPR55, peroxisome proliferatoractivated receptor gamma nuclear receptor, and Transient Receptor Potential Ankyrin 1 (TRPA1) and Transient Receptor Potential Vannilloid-type 2 (TRPV2) cation channels at >1 µm. [8] In the last years "photopharmacology" has rapidly emerged and found remarkable application for the control of biological functions by light with the unprecedented spatio-temporal solution that was made possible by chemical photoswitches that are incorporated into biologically active molecules...

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Photochromic Dopamine Receptor Ligands Based on Dithienylethenes and Fulgides

Cited by 43 publications

References 67 publications

Hemithioindigos for Cellular Photopharmacology: Desymmetrised Molecular Switch Scaffolds Enabling Design Control over the Isomer‐Dependency of Potent Antimitotic Bioactivity

Hemithioindigos for Cellular Photopharmacology: Desymmetrised Molecular Switch Scaffolds Enabling Design Control over the Isomer‐Dependency of Potent Antimitotic Bioactivity

Fulgimides as Light‐Activated Tools in Biological Investigations

The First Photochromic Affinity Switch for the Human Cannabinoid Receptor 2

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