Aliphatic Azides as Selective Cysteine Labeling Reagents for Integral Membrane Proteins

Szymanski, Dennis; Papanastasiou, Malvina; Pandarinathan, Lakshmipathi; Zvonok, Nikolai; Janero, David R.; Pavlopoulos, Spiro; Vouros, Paul; Makriyannis, Alexandros

doi:10.1021/acs.jmedchem.8b01302

Cited by 8 publications

(14 citation statements)

References 31 publications

(58 reference statements)

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“…Scheme8.Various reaction pathways arising from the photoactivation and subsequent intramolecular and biomolecular reactivity of aliphatic azides. [92] Chem.E ur.J. 2020,26,[33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] www.chemeurj.org ling of proteins with aliphatic azides.…”

Section: Aliphatic Azidesmentioning

confidence: 99%

“…Scheme8.Various reaction pathways arising from the photoactivation and subsequent intramolecular and biomolecular reactivity of aliphatic azides. [92] Chem.E ur.J.2020, 26,33-48 www.chemeurj.org 2020 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim 41 Concept ling of proteins with aliphatic azides. [92] They concluded that direct nitrene-insertionp roductsw ere not observed in the system and that site-specific and chemoselective labelling of cysteiner esidues through a1 ,2-alkyl shift mechanism wasf avoured.A liphatic azides have yet to be explored as reagents for bimolecular protein conjugation but their tendency to react with solvents and undergo facile intersystem crossing to give triplet speciesa re potentiald rawbacks.…”

Section: Aliphatic Azidesmentioning

confidence: 99%

“… Various reaction pathways arising from the photoactivation and subsequent intramolecular and biomolecular reactivity of aliphatic azides …”

Section: Photoactive Reagents That Produce Electrophilesmentioning

confidence: 99%

“…2020,26,[33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] www.chemeurj.org ling of proteins with aliphatic azides. [92] They concluded that direct nitrene-insertionp roductsw ere not observed in the system and that site-specific and chemoselective labelling of cysteiner esidues through a1 ,2-alkyl shift mechanism wasf avoured.A liphatic azides have yet to be explored as reagents for bimolecular protein conjugation but their tendency to react with solvents and undergo facile intersystem crossing to give triplet speciesa re potentiald rawbacks. Nevertheless, the possibility of achieving both chemo-and regioselective coupling to proteins (albeit through ap re-association pathway)i sa na ttractive feature of aliphatic azide photochemistry.…”

Section: Aliphatic Azidesmentioning

confidence: 99%

“…Syzmanski et al. performed detailed mechanistic studies on the various reaction products derived from photoactivated labelling of proteins with aliphatic azides . They concluded that direct nitrene‐insertion products were not observed in the system and that site‐specific and chemoselective labelling of cysteine residues through a 1,2‐alkyl shift mechanism was favoured.…”

Section: Photoactive Reagents That Produce Electrophilesmentioning

confidence: 99%

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Photochemical Reactions in the Synthesis of Protein–Drug Conjugates

Holland

Gut

Klingler

et al. 2019

Chemistry A European J

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The ability to modify biologically active molecules such as antibodies with drug molecules, fluorophores or radionuclides is crucial in drug discovery and target identification. Classic chemistry used for protein functionalisation relies almost exclusively on thermochemically mediated reactions. Our recent experiments have begun to explore the use of photochemistry to effect rapid and efficient protein functionalisation. This article introduces some of the principles and objectives of using photochemically activated reagents for protein ligation. The concept of simultaneous photoradiosynthesis of radiolabelled antibodies for use in molecular imaging is introduced as a working example. Notably, the goal of producing functionalised proteins in the absence of pre‐association (non‐covalent ligand‐protein binding) introduces requirements that are distinct from the more regular use of photoactive groups in photoaffinity labelling. With this in mind, the chemistry of thirteen different classes of photoactivatable reagents that react through the formation of intermediate carbenes, electrophiles, dienes, or radicals, is assessed.

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“…Scheme8.Various reaction pathways arising from the photoactivation and subsequent intramolecular and biomolecular reactivity of aliphatic azides. [92] Chem.E ur.J. 2020,26,[33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] www.chemeurj.org ling of proteins with aliphatic azides.…”

Section: Aliphatic Azidesmentioning

confidence: 99%

“…Scheme8.Various reaction pathways arising from the photoactivation and subsequent intramolecular and biomolecular reactivity of aliphatic azides. [92] Chem.E ur.J.2020, 26,33-48 www.chemeurj.org 2020 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim 41 Concept ling of proteins with aliphatic azides. [92] They concluded that direct nitrene-insertionp roductsw ere not observed in the system and that site-specific and chemoselective labelling of cysteiner esidues through a1 ,2-alkyl shift mechanism wasf avoured.A liphatic azides have yet to be explored as reagents for bimolecular protein conjugation but their tendency to react with solvents and undergo facile intersystem crossing to give triplet speciesa re potentiald rawbacks.…”

Section: Aliphatic Azidesmentioning

confidence: 99%

“… Various reaction pathways arising from the photoactivation and subsequent intramolecular and biomolecular reactivity of aliphatic azides …”

Section: Photoactive Reagents That Produce Electrophilesmentioning

confidence: 99%

Section: Aliphatic Azidesmentioning

confidence: 99%

Section: Photoactive Reagents That Produce Electrophilesmentioning

confidence: 99%

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Photochemical Reactions in the Synthesis of Protein–Drug Conjugates

Holland

Gut

Klingler

et al. 2019

Chemistry A European J

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Functionalized Cannabinoid Subtype 2 Receptor Ligands: Fluorescent, PET, Photochromic and Covalent Molecular Probes

2020

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Cannabinoid subtype 2 receptors (CB 2 Rs) are G protein‐coupled receptors (GPCRs) belonging to the endocannabinoid system, a complex network of signalling pathways leading to the regulation of key physiological processes. Interestingly, CB 2 Rs are strongly up‐regulated in pathological conditions correlated with the onset of inflammatory events like cancer and neurodegenerative diseases. Therefore, CB 2 Rs represent an important biological target for therapeutic as well as diagnostic purposes. No CB 2 R‐selective drugs are yet on the market, thus underlining a that deeper comprehension of CB 2 Rs’ complex activation pathways and their role in the regulation of diseases is needed. Herein, we report an overview of pharmacological and imaging tools such as fluorescent, positron emission tomography (PET), photochromic and covalent selective CB 2 R ligands. These molecular probes can be used in vitro as well as in vivo to investigate and explore the unravelled role(s) of CB 2 Rs, and they can help to design suitable CB 2 R‐targeted drugs.

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Novel Functionalized Cannabinoid Receptor Probes: Development of Exceptionally Potent Agonists

Jiang¹,

Iliopoulos‐Tsoutsouvas²,

Tong³

et al. 2021

J. Med. Chem.

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We report the development of novel cannabinergic probes that can stabilize the cannabinoid receptors (CBRs) through tight binding interactions. Ligand design involves the introduction of select groups at a judiciously chosen position within the classical hexahydrocannabinol template (monofunctionalized probes). Such groups include the electrophilic isothiocyanato, the photoactivatable azido, and the polar cyano moieties. These groups can also be combined to produce bifunctionalized probes potentially capable of interacting at two distinct sites within the CBR-binding domains. These novel compounds display remarkably high binding affinities for CBRs and are exceptionally potent agonists. A key ligand (27a, AM11245) exhibits exceptionally high potency in both in vitro and in vivo assays and was designated as “megagonist,” a property attributed to its tight binding profile. By acting both centrally and peripherally, 27a distinguishes itself from our previously reported “megagonist” AM841, whose functions are restricted to the periphery.

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Aliphatic Azides as Selective Cysteine Labeling Reagents for Integral Membrane Proteins

Cited by 8 publications

References 31 publications

Photochemical Reactions in the Synthesis of Protein–Drug Conjugates

Photochemical Reactions in the Synthesis of Protein–Drug Conjugates

Functionalized Cannabinoid Subtype 2 Receptor Ligands: Fluorescent, PET, Photochromic and Covalent Molecular Probes

Novel Functionalized Cannabinoid Receptor Probes: Development of Exceptionally Potent Agonists

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