-
Nature Oct 2022The ubiquitin E3 ligase substrate adapter cereblon (CRBN) is a target of thalidomide and lenalidomide, therapeutic agents used in the treatment of haematopoietic...
The ubiquitin E3 ligase substrate adapter cereblon (CRBN) is a target of thalidomide and lenalidomide, therapeutic agents used in the treatment of haematopoietic malignancies and as ligands for targeted protein degradation. These agents are proposed to mimic a naturally occurring degron; however, the structural motif recognized by the thalidomide-binding domain of CRBN remains unknown. Here we report that C-terminal cyclic imides, post-translational modifications that arise from intramolecular cyclization of glutamine or asparagine residues, are physiological degrons on substrates for CRBN. Dipeptides bearing the C-terminal cyclic imide degron substitute for thalidomide when embedded within bifunctional chemical degraders. Addition of the degron to the C terminus of proteins induces CRBN-dependent ubiquitination and degradation in vitro and in cells. C-terminal cyclic imides form adventitiously on physiologically relevant timescales throughout the human proteome to afford a degron that is endogenously recognized and removed by CRBN. The discovery of the C-terminal cyclic imide degron defines a regulatory process that may affect the physiological function and therapeutic engagement of CRBN.
Topics: Humans; Asparagine; Dipeptides; Glutamine; Imides; Lenalidomide; Ligands; Peptide Hydrolases; Proteolysis; Proteome; Thalidomide; Ubiquitination; Ubiquitin-Protein Ligase Complexes; Amino Acid Motifs; Cyclization
PubMed: 36261529
DOI: 10.1038/s41586-022-05333-5 -
Nutrients Aug 2022Diets rich in cruciferous vegetables have been associated with a lower risk of incidence and progression of prostate cancer. Sulforaphane, an isothiocyanate derived from... (Randomized Controlled Trial)
Randomized Controlled Trial
Diets rich in cruciferous vegetables have been associated with a lower risk of incidence and progression of prostate cancer. Sulforaphane, an isothiocyanate derived from 4-methylsulphinylbutyl glucosinolate (glucoraphanin) that accumulates in certain of these vegetables, notably broccoli, has been implicated in their protective effects. Likewise, the consumption of garlic and its sulphur-containing compounds such as alliin have been associated with a reduction in risk of prostate cancer. In this study, we tested whether consuming glucoraphanin derived from broccoli seeds and alliin derived from garlic resulted in the occurrence of these potential bioactive compounds in the prostate, which may contribute to our understanding of the putative protective effects of these dietary components. We recruited 42 men scheduled for a trans-perineal prostate biopsy into a randomised, double-blinded, 2 × 2-factorial dietary supplement four-week intervention study, and 39 completed the study. The two active interventions were supplements providing glucoraphanin from broccoli (BroccoMax®) and alliin from garlic (Kwai Heartcare®). Following the intervention, prostate biopsy tissue was analysed for the presence of sulforaphane and its thiol conjugates and for alliin and associated metabolites. Sulforaphane occurred in significantly higher levels in the prostate tissue (both within the transition and peripheral zone) of men consuming the glucoraphanin containing supplements (p < 0.0001) compared to men not consuming these supplements. However, while alliin and alliin-derived metabolites were detected within the prostate, there was no significant difference in the concentrations of these compounds in the prostate of men consuming supplements derived from garlic compared to men not consuming these supplements.
Topics: Allium; Antioxidants; Brassica; Cysteine; Glucosinolates; Humans; Imidoesters; Isothiocyanates; Male; Prostate; Prostatic Neoplasms; Sulfoxides
PubMed: 36014767
DOI: 10.3390/nu14163263 -
International Journal of Molecular... May 2022F Nuclear Magnetic Resonance spin-lattice relaxation experiments have been performed for a series of ionic liquids including the same anion,...
F Nuclear Magnetic Resonance spin-lattice relaxation experiments have been performed for a series of ionic liquids including the same anion, bis(trifluoromethanesulfonyl)imide, and cations with alkyl chains of different lengths: triethylhexylammonium, triethyloctylammonium decyltriethylammonium, dodecyltriethylammonium, decyltriethylammonium, and hexadecyltriethylammonium. The experiments have been carried out in a frequency range of 10 kHz to 10 MHz versus temperature. A thorough analysis of the relaxation data has led to the determination of the cation-anion as a relative translation diffusion coefficient. The diffusion coefficients have been compared with the corresponding cation-cation and anion-anion diffusion coefficients, revealing a correlation in the relative translation movement of the anion and the triethylhexylammonium, triethyloctylammonium, decyltriethylammonium, and dodecyltriethylammonium cations, whereas the relative translation diffusion between the anion and the cations with the longer alkyl chains, decyltriethylammonium and hexadecyltriethylammonium, remains rather uncorrelated (correlated to a much lesser extent).
Topics: Anions; Cations; Diffusion; Imides; Ionic Liquids
PubMed: 35682674
DOI: 10.3390/ijms23115994 -
Molecules (Basel, Switzerland) Feb 2021Novel polymer composites based on polyamide-imide Torlon and deep eutectic solvent (DES) were fabricated and adapted for separation processes. DES composed of zinc...
Novel polymer composites based on polyamide-imide Torlon and deep eutectic solvent (DES) were fabricated and adapted for separation processes. DES composed of zinc chloride and acetamide in a ratio of 1:3 M was first chosen as a Torlon-modifier due to the possibility of creating composites with a uniform filling of the DES through the formation of hydrogen bonds. The structure of the membranes was investigated by scanning electron microscopy and X-ray diffraction analysis; thermal stability was determined by thermogravimetric analysis and mass spectrometry. The surface of the composites was studied by determining the contact angles and calculating the surface tension. The transport properties were investigated by such membrane methods as pervaporation and gas separation. It was found that the inclusion of DES in the polymer matrix leads to a significant change in the structure and surface character of composites. It was also shown that DES plays the role of a plasticizer and increases the separation performance in the separation of liquids and gases. Torlon/DES composites with a small amount of modifier were effective in alcohol dehydration, and were permeable predominantly to water impurities in isopropanol. Torlon/DES-5 demonstrates high selectivity in the gas separation of O/N mixture.
Topics: Gases; Imides; Mass Spectrometry; Molecular Conformation; Nitrogen; Nylons; Oxygen; Permeability; Solvents; Surface Tension; Temperature; Thermogravimetry; Water; X-Ray Diffraction
PubMed: 33668455
DOI: 10.3390/molecules26040990 -
Journal of the American Chemical Society Jul 2022Sulfur functional groups are common motifs in bioactive molecules. Sulfonamides are most prevalent but related aza-derivatives, in which oxygen atoms are replaced by...
Sulfur functional groups are common motifs in bioactive molecules. Sulfonamides are most prevalent but related aza-derivatives, in which oxygen atoms are replaced by imidic nitrogens, such as sulfoximines and sulfonimidamides, are gaining attraction. Despite this activity, the double aza-variants of sulfonamides, termed sulfondiimidamides, are almost completely absent from the literature. The reason for this is poor synthetic accessibility. Although a recent synthesis has established sulfondiimidamides as viable motifs, the length of the route and the capricious nature of the key sulfondiimidoyl fluoride intermediates mean that direct application to discovery chemistry is challenging. Herein, we describe a two-step synthesis of sulfondiimidamides, exploiting a hypervalent iodine-mediated amination as the key step. The starting materials are organometallic reagents, an unsymmetrical sulfurdiimide, and amines. The method allowed >40 examples to be prepared, including derivatives of three sulfonamide-based drugs. The operational simplicity, broad scope, and concise nature make this route attractive for discovery chemistry applications.
Topics: Amination; Amines; Imides; Indicators and Reagents; Sulfonamides
PubMed: 35729783
DOI: 10.1021/jacs.2c04404 -
Seminars in Oncology Feb 2016With the properties of efficacy, safety, tolerability, practicability and low cost, foods containing bioactive phytochemicals are gaining significant attention as... (Review)
Review
With the properties of efficacy, safety, tolerability, practicability and low cost, foods containing bioactive phytochemicals are gaining significant attention as elements of chemoprevention strategies against cancer. Sulforaphane [1-isothiocyanato-4-(methylsulfinyl)butane], a naturally occurring isothiocyanate produced by cruciferous vegetables such as broccoli, is found to be a highly promising chemoprevention agent against not only a variety of cancers such as breast, prostate, colon, skin, lung, stomach or bladder, but also cardiovascular disease, neurodegenerative diseases, and diabetes. For reasons of experimental exigency, preclinical studies have focused principally on sulforaphane itself, while clinical studies have relied on broccoli sprout preparations rich in either sulforaphane or its biogenic precursor, glucoraphanin. Substantive subsequent evaluation of sulforaphane pharmacokinetics and pharmacodynamics has been undertaken using either pure compound or food matrices. Sulforaphane affects multiple targets in cells. One key molecular mechanism of action for sulforaphane entails activation of the Nrf2-Keap1 signaling pathway although other actions contribute to the broad spectrum of efficacy in different animal models. This review summarizes the current status of pre-clinical chemoprevention studies with sulforaphane and highlights the progress and challenges for the application of foods rich in sulforaphane and/or glucoraphanin in the arena of clinical chemoprevention.
Topics: Animals; Anticarcinogenic Agents; Brassica; Chemoprevention; Glucosinolates; Humans; Imidoesters; Isothiocyanates; NF-E2-Related Factor 2; Neoplasms; Oximes; Signal Transduction; Sulfoxides; Vegetables
PubMed: 26970133
DOI: 10.1053/j.seminoncol.2015.09.013 -
Blood Apr 1983Fifteen compounds reported to be inhibitors of gelation or sickling were studied by standard methods. These tests included (1) the determination of the solubility of... (Comparative Study)
Comparative Study Review
Fifteen compounds reported to be inhibitors of gelation or sickling were studied by standard methods. These tests included (1) the determination of the solubility of deoxyhemoglobin S or Csat, (2) evaluation of sickling in whole SS blood at various pO2s, (3) measurement of the oxygen affinity of hemoglobin and blood, and (4) examination of red cell indices and morphology. Among the 4 noncovalent agents tested, butylurea was the most potent inhibitor of gelation and sickling in vitro; however, relatively high concentrations were required compared to the covalent agents. In the latter group, bis-(3,5 dibromosalicyl)-fumarate, nitrogen mustard, and dimethyladipimidate were especially effective inhibitors of gelation and/or sickling. All of these compounds require further development before they can be considered for clinical use.
Topics: Anemia, Sickle Cell; Antisickling Agents; Aspirin; Azepines; Carbamyl Phosphate; Cyanates; Cystamine; Dimethyl Adipimidate; Drug Evaluation; Erythrocyte Indices; Glyceraldehyde; Hemoglobins; Humans; Imidoesters; Mechlorethamine; Oxygen Consumption; Phenylalanine; Pyridoxal; Solubility; Urea
PubMed: 6338971
DOI: No ID Found -
Adipocyte 2018Obesity is a low-grade sustained inflammatory state that causes oxidative stress in different metabolic tissues, which leads to insulin resistance and nonalcoholic fatty... (Review)
Review
Obesity is a low-grade sustained inflammatory state that causes oxidative stress in different metabolic tissues, which leads to insulin resistance and nonalcoholic fatty liver disease (NAFLD). Particularly, obesity-induced metabolic endotoxemia plays an important role in the pathogenesis of insulin resistance and inflammation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of antioxidant signaling that serves as a primary cellular defense against the cytotoxic effects of oxidative stress. Pharmacological stimulation of Nrf2 mitigates obesity and insulin resistance in mice; however, Nrf2 activators are not clinically available due to biosafety concerns. A recent study demonstrated that glucoraphanin, a precursor of the Nrf2 activator sulforaphane, ameliorates obesity by enhancing energy expenditure and browning of white adipose tissue, and attenuates obesity-related inflammation and insulin resistance by polarizing M2 macrophages and reducing metabolic endotoxemia. Thus, this review focuses on the efficiency and safety of glucoraphanin in alleviating obesity, insulin resistance, and NAFLD. Abbreviations: ALT, Alanine aminotransferase; AMPK, AMP-activated protein kinase; ATMs, Adipose tissue macrophages; BAT, Brown adipose tissue; CDDO-Im, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid-imidazolide; CDDO-Me, CDDO-methyl ester; DIO, High-fat-diet-induced obese; FFA, Free fatty acid; FGF, Fibroblast growth factor; GTP, Glutamyl transpeptidase; HFD, High-fat diet; IKKβ, Inhibitor of κB-kinase β; IL, Interleukin; JNK, C-Jun N-terminal kinase; KD, Knockdown; Keap1, Kelch-like ECH-associated protein 1; KO, Knockout; LPS, Lipopolysaccharide; NADPH, Nicotinamide adenine dinucleotide phosphate; NAFLD, Non-alcoholic fatty liver disease; NF-κB, Nuclear factor-κB; Nrf2, Nuclear factor E2-related factor 2; ROS, Reactive oxygen species; T2D, Type 2 diabetes; TLR, Toll-like receptor; TNF, tumor necrosis factor; UCP, Uncoupling protein; WAT, White adipose tissue.
Topics: Animals; Brassica; Endotoxemia; Glucosinolates; Imidoesters; Inflammation; Insulin Resistance; Macrophages; Obesity; Oximes; Seedlings; Sulfoxides
PubMed: 29898626
DOI: 10.1080/21623945.2018.1474669 -
Nucleic Acids Research Nov 1979The proteins of 30S RNP particles containing pre-mRNA (hnRNA) were cross-linked with bifunctional reagents (dimethyl-suberimidate and...
The proteins of 30S RNP particles containing pre-mRNA (hnRNA) were cross-linked with bifunctional reagents (dimethyl-suberimidate and dimethyl-3,3'-dithiobispropionimidate). Further treatment with 1 or 2 M NaCl dissociates all RNA from protein. However, a significant part of protein particles--informofers being cross-linked survived high salt treatment. Their sedimentation coefficients were close to those of original particles. No RNA could be detected in the informofers even after labeling the cells with a precursor for a long period of time. Sodium dodecylsulfate or urea dissociated cross-linked informofers into oligomeric polypeptides. They could be dissociated by beta-mercaptoethanol treatment if a reversible cross-linked reagent had been used. The resulting polypeptides were represented by informatin. RNP particles (30S RNP or poly-particles) were reconstituted upon mixing of cross-linked informofers with pre-mRNA and removal of 2 M NaCl.
Topics: Animals; Carcinoma, Ehrlich Tumor; Cross-Linking Reagents; Dimethyl Suberimidate; Disulfides; Electrophoresis, Polyacrylamide Gel; Imidoesters; Liver; Mice; Molecular Weight; Nucleoproteins; RNA, Messenger; Rats; Ribonucleoproteins
PubMed: 503864
DOI: 10.1093/nar/7.6.1649 -
Biochimica Et Biophysica Acta Aug 2010Sirtuins are ancient proteins widely distributed in all lifeforms of earth. These proteins are universally able to bind NAD(+), and activate it to effect... (Review)
Review
Sirtuins are ancient proteins widely distributed in all lifeforms of earth. These proteins are universally able to bind NAD(+), and activate it to effect ADP-ribosylation of cellular nucleophiles. The most commonly observed sirtuin reaction is the ADP-ribosylation of acetyllysine, which leads to NAD(+)-dependent deacetylation. Other types of ADP-ribosylation have also been observed, including protein ADP-ribosylation, NAD(+) solvolysis and ADP-ribosyltransfer to 5,6-dimethylbenzimidazole, a reaction involved in eubacterial cobalamin biosynthesis. This review broadly surveys the chemistries and chemical mechanisms of these enzymes.
Topics: Acetylation; Adenosine Diphosphate Ribose; Animals; Benzimidazoles; Humans; Imidoesters; Lysine; Models, Biological; Molecular Structure; NAD; Niacinamide; Plasmodium falciparum; Saccharomyces cerevisiae; Sirtuins; Trypanosoma brucei brucei
PubMed: 20132909
DOI: 10.1016/j.bbapap.2010.01.021