Synthesis of Diazirine‐Based Photoreactive Saccharin Derivatives for the Photoaffinity Labeling of Gustatory Receptors

Wang, Lei; Yoshida, Takuma; Muto, Yasuyuki; Murai, Yuta; Tachrim, Zetryana Puteri; Ishida, Akiko; Nakagawa, Souichi; Sakihama, Yasuko; Hashidoko, Yasuyuki; Masuda, Koichi; Hatanaka, Y.; Hashimoto, Makoto

doi:10.1002/ejoc.201500184

Cited by 20 publications

(24 citation statements)

References 27 publications

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“…[69,70] Am ajor advance in the use of aryl diazirines for PALw as achieved in 1980 when Brunner et al reported the efficient synthesis and photochemical properties of para-substituted trifluoromethyl phenyld iazirines-reagents whichh ave become the mainstay of most modern applicationso fP AL. [23] Recent examples which highlight the synthetic versatility of incorporating trifluoromethyl phenyld iazirines into complex structures include ( Figure 4): the synthesis of ap hotoactivatable version of the potent topoisomerase II inhibitor etoposide (compound 8); [71] ap hotoactivatable derivative of the artificial sweetener saccharin for potential use in elucidating the mechanismst hat underpin our sense of taste (compound 9); [72] and ap hotoactivatable version of the heat-shock protein 90 (HSP90) inhibitor novobiocin (compound 10)f or elucidating the mechanism of drug binding to the C-terminal protein domain. [73]…”

Section: Aryl Diazirinesmentioning

confidence: 99%

“…Synthesis of aliphatic diazirines is straightforward and can be readily accomplished in high yields by using the improved methods reported by Wang et al [78] As mentioneda bove,t he propensity of aliphatic diazirines to undergo rapid b-H atom transfer leading to an alkene product, as well as photoinitiated rearrangement to give the diazo isomer which undergoes nucleophilic reactions with the solvent, are major limitations of Structures of recent photoactiveprobesused to study the mechanismsofa ction for different anti-cancerd rugs and artificial protein substrates. [71][72][73] Chem. Eur.J.…”

Section: Aliphatic Diazirinesmentioning

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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Section: Aryl Diazirinesmentioning

confidence: 99%

Section: Aliphatic Diazirinesmentioning

confidence: 99%

Photochemical Reactions in the Synthesis of Protein–Drug Conjugates

Holland

Gut

Klingler

et al. 2019

Chemistry A European J

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“…Photoaffinity labeling [ 1 , 2 , 3 , 4 , 5 ] has emerged as a powerful methodology in the field of biology due to its availability for elucidating the interactions between bioactive molecules and proteins. Various photophores—including phenyl azides, benzophenones, and diazirines—are commonly employed in this field [ 6 , 7 , 8 , 9 , 10 , 11 ]. Under UV irradiation, photophores are converted into highly reactive intermediates which can form covalent bonds between ligands and proteins.…”

Section: Introductionmentioning

confidence: 99%

Base-Mediated One-Pot Synthesis of Aliphatic Diazirines for Photoaffinity Labeling

et al. 2017

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Aliphatic diazirines have been widely used as prominent photophores for photoaffinity labeling owing to their relatively small size which can reduce the steric effect on the natural interaction between ligands and proteins. Based on our continuous efforts to develop efficient methods for the synthesis of aliphatic diazirines, we present here a comprehensive study about base-mediated one-pot synthesis of aliphatic diazirines. It was found that potassium hydroxide (KOH) can also promote the construction of aliphatic diazirine with good efficiency. Importantly, KOH is cheaper, highly available, and easily handled and stored compared with the previously used base, potassium tert-butoxide (t-BuOK). Gram-scale study showed that it owned great advantages in being used for the large-scale production of aliphatic diazirines. This protocol is highly neat and the desired products can be easily isolated and purified. As the first comprehensive study of the base-mediated one-pot synthesis of aliphatic diazirines, this work provided good insight into the preparation and utilization of diazirine-based photoaffinity labeling probes.

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“…21,23 Lastly, diaziridine 1.4 can be oxidised to diazirine 1.5 under a suite of conditions, including iodine and triethylamine. 24 These TPD routes are well established and can produce near quantitative yields.…”

Section: Tpd Synthesismentioning

confidence: 99%

“…These TPD routes are well established and can produce near quantitative yields. 24 It should be noted that reaction between the trifluoromethyl ketone, ammonia and HOSA, as used for aliphatic diaziridines, is reported to form a stable hemiaminal adduct which does not readily undergo dehydration. 228 Scheme 7.3.…”

Section: Photoaffinity Labellingmentioning

confidence: 99%

Teaching old molecules new tricks: repurposing investigational drugs as chemical probes

Hill¹

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This thesis revolves around two investigational drugs with remarkable biological activity, MCC950 and PD-132301. MCC950 inhibits the NOD-like receptor protein 3 (NLRP3) inflammasomean emerging drug target implicated in a diverse array of diseases, including several neurological conditions. PD-132301 is an inhibitor of sterol O-acyltransferase 1 (SOAT1)an enzyme previously thought to modulate atherosclerotic plaque formation. The development of both compounds was abandoned due to toxicity concerns and limited knowledge of the biological pathways. By understanding the shortcomings of these compounds, they can be repurposed and redesigned as chemical probes of diseases with unmet clinical needs. Chapter 1 introduces chemical probes, including photoaffinity and positron emission tomography (PET) probes, and how they can be used in target identification and biodistribution studies. The NLRP3 inflammasome pathway and the rationale behind developing NLRP3 inhibitor drugs are also discussed. Chapter 2 focuses on identifying the molecular target of MCC950. The design and synthesis of two MCC950-based photoaffinity probes are described. These probes are evaluated in cell-based assays, as both NLRP3 inhibitors and target identification tools. Both photoaffinity probes suggest a direct interaction with NLRP3 itself. This finding, together with independent and collaborator research, furthers our understanding of how NLRP3 inhibitors ameliorate inflammatory diseases. Chapter 3 describes the evaluation of MCC950 brain uptake using PET imaging. Carrier added [ 11 C]CO2 fixation chemistry was used to synthesise [ 11 C]MCC950. [ 11 C]MCC950 brain uptake was evaluated in healthy mouse, rat, and monkey PET studies. At microdoses, low molar activity [ 11 C]MCC950 exhibited poor brain uptake and rapid washout and therefore appears to be a poor neuroimaging agent in healthy subjects. Although low molar activity [ 11 C]MCC950 does not appear useful for in vivo imaging in healthy subjects, this work facilitates 11 C-labelling of similar analogues. Attempts to synthesise [ 18 F]Fluoro-MCC950 are also described. Chapter 4 investigates the repurposing of SOAT1 inhibitors for atherosclerosis PET imaging. [ 11 C]PD-132301 was synthesised via [ 11 C]methylation, while [ 18 F]4.1 was synthesised via aromatic [ 18 F]fluorination. Evaluation in ex vivo rat biodistribution studies suggests that [ 11 C]PD-132301 is more selective for SOAT1. Using PET imaging, [ 11 C]PDii 132301 identified aortic atherosclerosis in apolipoprotein E deficient mice. This work suggests SOAT1 inhibitors are worthy of further investigation as atherosclerosis imaging probes. Chapter 5 summarises this work in the context of repurposing compounds as chemical probes.

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Synthesis of Diazirine‐Based Photoreactive Saccharin Derivatives for the Photoaffinity Labeling of Gustatory Receptors

Cited by 20 publications

References 27 publications

Photochemical Reactions in the Synthesis of Protein–Drug Conjugates

Photochemical Reactions in the Synthesis of Protein–Drug Conjugates

Base-Mediated One-Pot Synthesis of Aliphatic Diazirines for Photoaffinity Labeling

Teaching old molecules new tricks: repurposing investigational drugs as chemical probes

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