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Nature Chemical Biology May 2020We recently described glutathione peroxidase 4 (GPX4) as a promising target for killing therapy-resistant cancer cells via ferroptosis. The onset of therapy resistance...
We recently described glutathione peroxidase 4 (GPX4) as a promising target for killing therapy-resistant cancer cells via ferroptosis. The onset of therapy resistance by multiple types of treatment results in a stable cell state marked by high levels of polyunsaturated lipids and an acquired dependency on GPX4. Unfortunately, all existing inhibitors of GPX4 act covalently via a reactive alkyl chloride moiety that confers poor selectivity and pharmacokinetic properties. Here, we report our discovery that masked nitrile-oxide electrophiles, which have not been explored previously as covalent cellular probes, undergo remarkable chemical transformations in cells and provide an effective strategy for selective targeting of GPX4. The new GPX4-inhibiting compounds we describe exhibit unexpected proteome-wide selectivity and, in some instances, vastly improved physiochemical and pharmacokinetic properties compared to existing chloroacetamide-based GPX4 inhibitors. These features make them superior tool compounds for biological interrogation of ferroptosis and constitute starting points for development of improved inhibitors of GPX4.
Topics: Animals; Cell Line, Tumor; Enzyme Inhibitors; Ferroptosis; Humans; Lipid Peroxidation; Mice, SCID; Molecular Probes; Molecular Targeted Therapy; Nitriles; Oxides; Phospholipid Hydroperoxide Glutathione Peroxidase; Prodrugs; Rats, Wistar; Selenocysteine; Small Molecule Libraries; Structure-Activity Relationship
PubMed: 32231343
DOI: 10.1038/s41589-020-0501-5 -
Journal of Occupational Health Mar 2017Allyl nitrile (3-butenenitrile) occurs naturally in the environment, in particular, in cruciferous vegetables, indicating a possible daily intake of the compound. There... (Review)
Review
OBJECTIVES
Allyl nitrile (3-butenenitrile) occurs naturally in the environment, in particular, in cruciferous vegetables, indicating a possible daily intake of the compound. There is no report on actual health effects of allyl nitrile in humans, although it is possible that individuals in the environment are at a risk of exposure to allyl nitrile. However, little is known about its quantitative assessment for the environment and bioactivity in the body. This study provides a review of previous accumulated studies on allyl nitrile.
METHODS
Published literature on allyl nitrile was examined for findings on toxicity, metabolism, risk of various cancers, generation, intake estimates, and low-dose effects in the body.
RESULTS
High doses of allyl nitrile produce toxicity characterized by behavioral abnormalities, which are considered to be produced by an active metabolite, 3,4-epoxybutyronitrile. Cruciferous vegetables have been shown to have a potential role in reducing various cancers. Hydrolysis of the glucosinolate sinigrin, rich in cruciferous vegetables, results in the generation of allyl nitrile. An intake of allyl nitrile is estimated at 0.12 μmol/kg body weight in Japan. Repeated exposure to low doses of allyl nitrile upregulates antioxidant/phase II enzymes in various tissues; this may contribute to a reduction in neurotoxicity and skin inflammation. These high and low doses are far more than the intake estimate.
CONCLUSION
Allyl nitrile in the environment is a compound with diverse bioactivities in the body, characterized by inducing behavioral abnormalities at high doses and some antioxidant/phase II enzymes at low doses.
Topics: Animals; Antioxidants; Disease Models, Animal; Glucosinolates; Humans; Mental Disorders; Mice; Neoplasms; Nitriles; Rats; Vegetables
PubMed: 28132970
DOI: 10.1539/joh.16-0147-RA -
Journal of the American Chemical Society Dec 2019The generation of pyridynes from diyne nitriles is reported. These cyano-containing precursors are analogues of the triyne substrates typically used for the...
The generation of pyridynes from diyne nitriles is reported. These cyano-containing precursors are analogues of the triyne substrates typically used for the hexadehydro-Diels-Alder (HDDA) cycloisomerization reactions that produce ring-fused benzynes. Hence, the new processes described represent aza-HDDA reactions. Depending on the location of the nitrile, either 3,4-pyridynes (from 1,3-diynes containing a tethered cyano group) or 2,3-pyridynes (from 1-cyanoethyne derivatives containing a tethered alkyne) are produced. In situ trapping of these reactive intermediates leads to highly substituted and functionalized pyridine derivatives. In several instances, unprecedented pyridyne trapping reactions are seen. Differences in reaction energetics between the aza-HDDA substrates and that of their analogous HDDA (triyne) substrates are discussed.
Topics: Aza Compounds; Density Functional Theory; Models, Molecular; Molecular Conformation; Nitriles
PubMed: 31789026
DOI: 10.1021/jacs.9b11243 -
Transplant International : Official... 2023Solid organ transplant (SOT) recipients have a higher risk of developing invasive mould diseases (IMD). Isavuconazole is a novel broad-spectrum azole active against... (Review)
Review
Solid organ transplant (SOT) recipients have a higher risk of developing invasive mould diseases (IMD). Isavuconazole is a novel broad-spectrum azole active against spp. and Mucor, well tolerated, with an excellent bioavailability and predictable pharmacokinetics, that penetrates in most tissues rapidly, and has few serious adverse effects, including hepatic toxicity. Contrary to other broad-spectrum azoles, such as voriconazole and posaconazole, isavuconazole appears to show significant smaller drug-drug interactions with anticalcineurin drugs. We have performed an extensive literature review of the experience with the use of isavuconazole in SOT, which included the SOTIS and the ISASOT studies, and published case reports. More than 140 SOT recipients treated with isavuconazole for IMD were included. Most patients were lung and kidney recipients treated for an infection. Isavuconazole was well tolerated (less than 10% of patients required treatment discontinuation). The clinical responses appeared comparable to that found in other high-risk patient populations. Drug-drug interactions with immunosuppressive agents were manageable after the reduction of tacrolimus and the adjustment of mTOR inhibitors at the beginning of treatment. In conclusion, isavuconazole appears to be a reasonable option for the treatment of IMD in SOT. More clinical studies are warranted.
Topics: Humans; Antifungal Agents; Aspergillosis; Nitriles; Organ Transplantation; Transplant Recipients; Voriconazole
PubMed: 38161768
DOI: 10.3389/ti.2023.11845 -
ChemistryOpen Oct 2022The generation of the quaternary stereocenter at the C9 position of salvinorin A precursors by the Claisen rearrangement was investigated. The required allyl alcohol was...
The generation of the quaternary stereocenter at the C9 position of salvinorin A precursors by the Claisen rearrangement was investigated. The required allyl alcohol was prepared from a Wieland-Miescher ketone using a known γ-hydroxylation, reduction of the enone double bond, cyanohydrin formation, and elimination, yielding an unsaturated nitrile. A two-step reduction led to the required allyl alcohol. The subsequent Johnson-Claisen rearrangement provided a mixture of two diastereomeric 1,4-unsaturated esters in a ratio of around 2.6 : 1. The major isomer could be converted to a key intermediate of the Hagiwara synthesis of salvinorin A.
Topics: Diterpenes, Clerodane; Esters; Ketones; Nitriles; Propanols; Stereoisomerism
PubMed: 35218166
DOI: 10.1002/open.202200015 -
Journal of the American Chemical Society May 2022Nitriles are widely used vibrational probes; however, the interpretation of their IR frequencies is complicated by hydrogen bonding (H-bonding) in protic environments....
Nitriles are widely used vibrational probes; however, the interpretation of their IR frequencies is complicated by hydrogen bonding (H-bonding) in protic environments. We report a new vibrational Stark effect (VSE) that correlates the electric field projected on the -C≡N bond to the transition dipole moment and, by extension, the nitrile peak area or integrated intensity. This linear VSE applies to H-bonding and non-H-bonding interactions. It can therefore be generally applied to determine electric fields in all environments. Additionally, it allows for semiempirical extraction of the H-bonding contribution to the blueshift of the nitrile frequency. Nitriles were incorporated at H-bonding and non-H-bonding protein sites using amber suppression, and each nitrile variant was structurally characterized at high resolution. We exploited the combined information available from variations in frequency and integrated intensity and demonstrate that nitriles are a generally useful probe for electric fields.
Topics: Electricity; Hydrogen Bonding; Nitriles; Proteins; Static Electricity
PubMed: 35467853
DOI: 10.1021/jacs.2c00675 -
Molecules (Basel, Switzerland) Nov 2022Glucosinolates, specialized metabolites of the Brassicales including crops and , have attracted considerable interest as chemical defenses and health-promoting...
Glucosinolates, specialized metabolites of the Brassicales including crops and , have attracted considerable interest as chemical defenses and health-promoting compounds. Their biological activities are mostly due to breakdown products formed upon mixing with co-occurring myrosinases and specifier proteins, which can result in multiple products with differing properties, even from a single glucosinolate. Whereas product profiles of aliphatic glucosinolates have frequently been reported, indole glucosinolate breakdown may result in complex mixtures, the analysis of which challenging. The aim of this study was to assess the breakdown of indole glucosinolates in root and rosette homogenates and to test the impact of nitrile-specifier proteins (NSPs) on product profiles. To develop a GC-MS-method for quantification of carbinols and nitriles derived from three prominent indole glucosinolates, we synthesized standards, established derivatization conditions, determined relative response factors and evaluated applicability of the method to plant homogenates. We show that carbinols are more dominant among the detected products in rosette than in root homogenates of wild-type and NSP1- or NSP3-deficient mutants. NSP1 is solely responsible for nitrile formation in rosette homogenates and is the major NSP for indolic nitrile formation in root homogenates, with no contribution from NSP3. These results will contribute to the understanding of the roles of NSPs in plants.
Topics: Arabidopsis; Glucosinolates; Methanol; Nitriles; Indoles
PubMed: 36432142
DOI: 10.3390/molecules27228042 -
The Journal of Biological Chemistry Aug 2012The enzyme QueF catalyzes the reduction of the nitrile group of 7-cyano-7-deazaguanine (preQ(0)) to 7-aminomethyl-7-deazaguanine (preQ(1)), the only nitrile reduction...
The enzyme QueF catalyzes the reduction of the nitrile group of 7-cyano-7-deazaguanine (preQ(0)) to 7-aminomethyl-7-deazaguanine (preQ(1)), the only nitrile reduction reaction known in biology. We describe here two crystal structures of Bacillus subtilis QueF, one of the wild-type enzyme in complex with the substrate preQ(0), trapped as a covalent thioimide, a putative intermediate in the reaction, and the second of the C55A mutant in complex with the substrate preQ(0) bound noncovalently. The QueF enzyme forms an asymmetric tunnel-fold homodecamer of two head-to-head facing pentameric subunits, harboring 10 active sites at the intersubunit interfaces. In both structures, a preQ(0) molecule is bound at eight sites, and in the wild-type enzyme, it forms a thioimide covalent linkage to the catalytic residue Cys-55. Both structural and transient kinetic data show that preQ(0) binding, not thioimide formation, induces a large conformational change in and closure of the active site. Based on these data, we propose a mechanism for the activation of the Cys-55 nucleophile and subsequent hydride transfer.
Topics: Amino Acid Substitution; Bacillus subtilis; Bacterial Proteins; Mutation, Missense; Nitriles; Oxidation-Reduction; Oxidoreductases
PubMed: 22787148
DOI: 10.1074/jbc.M112.388538 -
Molecules (Basel, Switzerland) Dec 2022In this work, we describe the design, synthesis, and structure-activity relationship of 6-(tetrazol-5-yl)-7-aminoazolo[1,5-a]pyrimidines as inhibitors of Casein kinase 2...
In this work, we describe the design, synthesis, and structure-activity relationship of 6-(tetrazol-5-yl)-7-aminoazolo[1,5-a]pyrimidines as inhibitors of Casein kinase 2 (CK2). At first, we optimized the reaction conditions for the azide-nitrile cycloaddition in the series of 6-cyano-7-aminoazolopyridimines and sodium azide. The regioselectivity of this process has been shown, as the cyano group of the pyrimidine cycle was converted to tetrazole while the nitrile of the azole fragment did not react. The desired tetrazolyl-azolopyrimidines were obtained in a moderate to excellent yields (42−95%) and converted further to water soluble sodium salts by the action of sodium bicarbonate. The obtained 6-(tetrazol-5-yl)-7-aminopyrazolo[1,5-a]pyrimidines 2a−k and their sodium salts 3a−c, 3g−k showed nano to low micromolar range of CK2 inhibition while corresponding [1,2,4]triazolopyrimidines 10a−k were less active (IC50 > 10 µM). The leader compound 3-phenyl-6-(tetrazol-5-yl)-7-aminopyrazolo[1,5-a]pyrimidine 2i as CK2 inhibitor showed IC50 45 nM.
Topics: Casein Kinase II; Salts; Drug Design; Structure-Activity Relationship; Tetrazoles; Pyrimidines; Nitriles; Sodium; Molecular Structure
PubMed: 36557833
DOI: 10.3390/molecules27248697 -
Journal of the American Chemical Society May 2016The use of small, natural chemical reporters in conjunction with catalyst-free bioorthogonal reactions will greatly streamline protein labeling in a cellular environment...
The use of small, natural chemical reporters in conjunction with catalyst-free bioorthogonal reactions will greatly streamline protein labeling in a cellular environment with minimum perturbation to their function. Here we report the discovery of a 2-cyanobenzothiazole (CBT)-reactive peptide tag, CX10R7, from a cysteine-encoded peptide phage library using the phage-assisted interrogation of reactivity method. Fusion of CX10R7 with a protein of interest allows site-specific labeling of the protein with CBT both in vitro and on the surface of E. coli cells. Mutagenesis studies indicated that the reactivity and specificity of CX10R7 are attributed to the sequence environment, in which the residues surrounding cysteine help to stabilize the ligation product.
Topics: Amino Acid Sequence; Benzothiazoles; Escherichia coli; Nitriles; Peptides
PubMed: 27082895
DOI: 10.1021/jacs.6b00982