In Situ Observation of Thiol Michael Addition to a Reversible Covalent Drug in a Crystalline Sponge

Duplan, Vincent; Hoshino, Manabu; Li, Wei; Honda, Tadashi; Fujita, Makoto

doi:10.1002/ange.201509801

Cited by 16 publications

(7 citation statements)

References 46 publications

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“…Should covalent inhibition of hGOAT by CDDO-EA (3) involve rapid formation of a noncovalent enzyme−inhibitor complex followed by a slower alkylation of a cysteine side chain thiol by the α- facilitated by the increased acidity of the α-hydrogen geminal to the cyano group. 59,61 We determined the reversibility of hGOAT inhibition by α-cyanoenone compounds 3 and 9 by enzyme pretreatment with each inhibitor at 3 times the measured IC 50 concentration, followed by a 10-fold dilution into either reaction buffer or buffer containing the same inhibitor concentration as the pretreatment (Figure 5d). NEM exhibits classical irreversible hGOAT inhibition, with no increase in hGOAT activity following inhibitor dilution.…”

Section: ■ Resultsmentioning

confidence: 99%

Synthetic Triterpenoid Inhibition of Human Ghrelin O-Acyltransferase: The Involvement of a Functionally Required Cysteine Provides Mechanistic Insight into Ghrelin Acylation

et al. 2017

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The peptide hormone ghrelin plays a key role in regulating hunger and energy balance within the body. Ghrelin signaling presents a promising and unexploited target for development of small-molecule therapeutics to treat obesity, diabetes, and other health conditions. Inhibition of ghrelin O-acyltransferase (GOAT), which catalyzes an essential octanoylation step in ghrelin maturation, offers a potential avenue for controlling ghrelin signaling. Through screening a small molecule library, we have identified a class of synthetic triterpenoids that efficiently inhibit ghrelin acylation by the human isoform of GOAT (hGOAT). These compounds function as covalent reversible inhibitors of hGOAT, providing the first evidence for involvement of a nucleophilic cysteine residue in substrate acylation by a MBOAT family acyltransferase. Surprisingly, the mouse form of GOAT does not exhibit susceptibility to cysteine modifying electrophiles revealing an important distinction in the activity and behavior between these closely related GOAT isoforms. This study establishes these compounds as potent small molecule inhibitors of ghrelin acylation and provides a foundation for the development of novel hGOAT inhibitors as therapeutics targeting diabetes and obesity.

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Section: ■ Resultsmentioning

confidence: 99%

Synthetic Triterpenoid Inhibition of Human Ghrelin O-Acyltransferase: The Involvement of a Functionally Required Cysteine Provides Mechanistic Insight into Ghrelin Acylation

et al. 2017

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“…After the simultaneous capture experiments described above, both types of contaminants were completely extracted from 2 by suspending, consecutively, the loaded material in 2-mercaptoethanol and ethanol for 4 and 2 h, respectively. The resulting material, with formula {Ca II 30. In order to determine the reusability of this material, 50 mg of this recycled polycrystalline sample of 2 was soaked in 20 mL of an aqueous solution containing 1 ppm of Hg(NO 3 ) 2 , Pb(NO 3 ) 2 , TlNO 3 , NaNO 3 , KNO 3 , Mg(NO 3 ) 2 , Ca(NO 3 ) 2 , Ni-(NO 3 ) 2 , and Cu(NO 3 ) 2 and 10 ppm of PY, AO, BG, and MB.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

Multivariate Metal–Organic Frameworks for the Simultaneous Capture of Organic and Inorganic Contaminants from Water

et al. 2019

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We report a new water-stable multivariate (MTV) metal–organic framework (MOF) prepared by combining two different oxamide-based metalloligands derived from the natural amino acids l-serine and l-methionine. This unique material features hexagonal channels decorated with two types of flexible and functional “arms” (−CH2OH and −CH2CH2SCH3) capable of enabling, synergistically, the simultaneous and efficient removal of both inorganic (heavy metals such as Hg2+, Pb2+, and Tl+) and organic (dyes such as Pyronin Y, Auramine O, Brilliant green, and Methylene blue) contaminants, and, in addition, this MTV-MOF is completely reusable. Single-crystal X-ray diffraction measurements allowed solving the crystal structure of a host–guest adsorbate, containing both HgCl2 and Methylene blue, and offered unprecedented snapshots of this unique dual capture process. This is the very first time that a MOF can be used for the removal of all sorts of pollutants from water resources, thus opening new perspectives for this emerging type of MTV-MOF.

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“… 3 − 7 Inclusion of molecular guests into MOFs during synthesis was already shown in the 1990s, 8 , 9 but with the crystalline sponge method they can be included after MOF synthesis by simply soaking the MOF host crystal in a solution containing the guest. The possibility to elucidate molecular structures, 10 − 22 as well as observing reaction mechanisms, 23 and reaction intermediates 24 makes the crystalline sponge method a unique tool for structure analysis, including absolute structure determination.…”

Section: Introductionmentioning

confidence: 99%

Racemic and Enantiopure Camphene and Pinene Studied by the Crystalline Sponge Method

Poel¹,

Tinnemans²,

Duchateau

et al. 2017

Crystal Growth & Design

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The use of an achiral metal–organic framework for structure determination of chiral compounds is demonstrated for camphene and pinene. The structure of enantiopure β-pinene can be resolved using the crystalline sponge method. However, α-pinene cannot be resolved using enantiopure material alone because no ordering of guest molecules takes place in that case. Interestingly, enantiomeric pairs order inside the channels of the host framework when impure (+)-camphene is offered to the host, which is also the case when a racemic mixture of α-pinene is used. A mixture of (+)-α-pinene and (−)-β-pinene also leads to ordered incorporation in the host, showing the influence of the presence of an inversion center in the host framework. We further show that powder X-ray diffraction provides a direct view on incorporation of ordered guest molecules. This technique, therefore, provides a way to determine the optimal and/or minimal soaking time. In contrast, color change of the crystal only demonstrates guest uptake, not ordering. Moreover, we show that color change can also be caused by guest-induced host degradation.

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In Situ Observation of Thiol Michael Addition to a Reversible Covalent Drug in a Crystalline Sponge

Cited by 16 publications

References 46 publications

Synthetic Triterpenoid Inhibition of Human Ghrelin O-Acyltransferase: The Involvement of a Functionally Required Cysteine Provides Mechanistic Insight into Ghrelin Acylation

Synthetic Triterpenoid Inhibition of Human Ghrelin O-Acyltransferase: The Involvement of a Functionally Required Cysteine Provides Mechanistic Insight into Ghrelin Acylation

Multivariate Metal–Organic Frameworks for the Simultaneous Capture of Organic and Inorganic Contaminants from Water

Racemic and Enantiopure Camphene and Pinene Studied by the Crystalline Sponge Method

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