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Molecular & Cellular Proteomics : MCP Oct 2014Plants produce hundreds of glycosidases. Despite their importance in cell wall (re)modeling, protein and lipid modification, and metabolite conversion, very little is...
Plants produce hundreds of glycosidases. Despite their importance in cell wall (re)modeling, protein and lipid modification, and metabolite conversion, very little is known of this large class of glycolytic enzymes, partly because of their post-translational regulation and their elusive substrates. Here, we applied activity-based glycosidase profiling using cell-permeable small molecular probes that react covalently with the active site nucleophile of retaining glycosidases in an activity-dependent manner. Using mass spectrometry we detected the active state of dozens of myrosinases, glucosidases, xylosidases, and galactosidases representing seven different retaining glycosidase families. The method is simple and applicable for different organs and different plant species, in living cells and in subproteomes. We display the active state of previously uncharacterized glycosidases, one of which was encoded by a previously declared pseudogene. Interestingly, glycosidase activity profiling also revealed the active state of a diverse range of putative xylosidases, galactosidases, glucanases, and heparanase in the cell wall of Nicotiana benthamiana. Our data illustrate that this powerful approach displays a new and important layer of functional proteomic information on the active state of glycosidases.
Topics: Arabidopsis; Arabidopsis Proteins; Aziridines; Catalytic Domain; Cell Wall; Cyclohexanols; Glycoside Hydrolases; Mass Spectrometry; Molecular Probes; Phylogeny; Proteomics
PubMed: 25056938
DOI: 10.1074/mcp.O114.041616 -
Current Urology Reports Oct 2018As our molecular understanding of bladder cancer continues to advance, more and more novel agents are entering clinical trials across the spectrum of bladder cancer... (Review)
Review
PURPOSE OF REVIEW
As our molecular understanding of bladder cancer continues to advance, more and more novel agents are entering clinical trials across the spectrum of bladder cancer stages. The clinical trial activity for non-muscle invasive bladder cancer (NMIBC) has been boosted further by the evolution of specific disease states that set more uniform inclusion criteria for clinical trial design. Here, we aimed to review the current clinical trials landscape in non-muscle invasive bladder cancer with respect to these disease states.
RECENT FINDINGS
Most active clinical trials focus on high-risk NMIBC in either the BCG-naïve or BCG-unresponsive setting. Strict criteria to define the disease state and a clear pathway to drug registration have encouraged trials for patients with BCG-unresponsive NMIBC. The most promising potential breakthroughs for BCG-naïve patients include alternative BCG strains, immune-priming with intradermal BCG vaccination, and systemic immune checkpoint blockade. The latter therapy is also being actively investigated in multiple trials in BCG-unresponsive NMIBC, along with novel viral agents such as INSTILADRIN (nadofaragene firadenovec) and targeted agents such as oportuzumab monatox. After many years of relative stagnation, multiple new therapies currently under investigation in well-designed clinical trials appear poised for routine clinical implementation in the near future. These therapies should dramatically improve the outcome of patients with NMIBC. We can look forward to the challenges of biomarker-driven drug selection, optimal drug sequencing, and rational combination therapies.
Topics: Adjuvants, Immunologic; Administration, Intravesical; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Immunological; Aziridines; BCG Vaccine; Carcinoma, Transitional Cell; Chemotherapy, Adjuvant; Clinical Trials as Topic; Combined Modality Therapy; Humans; Indolequinones; Injections, Intradermal; Mitomycin; Muscle, Smooth; Neoplasm Invasiveness; Polysaccharides, Bacterial; Proteins; Recombinant Fusion Proteins; Tamoxifen; Typhoid-Paratyphoid Vaccines; Urinary Bladder Neoplasms; Urologic Surgical Procedures
PubMed: 30357541
DOI: 10.1007/s11934-018-0852-6 -
Journal of the American Chemical Society Sep 2022Natural products containing an aziridine ring, such as mitomycin C and azinomycin B, exhibit antitumor activities by alkylating DNA via their aziridine rings; however,...
Natural products containing an aziridine ring, such as mitomycin C and azinomycin B, exhibit antitumor activities by alkylating DNA via their aziridine rings; however, the biosynthetic mechanisms underlying the formation of these rings have not yet been elucidated. We herein investigated the biosynthesis of vazabitide A, the structure of which is similar to that of azinomycin B, and demonstrated that Vzb10/11, with no similarities to known enzymes, catalyzed the formation of the aziridine ring via sulfate elimination. To elucidate the detailed reaction mechanism, crystallization of Vzb10/11 and the homologous enzyme, AziU3/U2, in the biosynthesis of azinomycin B was attempted, and the structure of AziU3/U2, which had a new protein fold overall, was successfully determined. The structural analysis revealed that these enzymes adjusted the dihedral angle between the amino group and the adjacent sulfate group of the substrate to almost 180° and enhanced the nucleophilicity of the C6-amino group temporarily, facilitating the S2-like reaction to form the aziridine ring. The present study reports for the first time the molecular basis for aziridine ring formation.
Topics: Aziridines; DNA; Mitomycin; Sulfates
PubMed: 35998388
DOI: 10.1021/jacs.2c07243 -
Molecular Diversity May 2018Aziridine ring opening reactions have gained tremendous importance in the synthesis of nitrogen containing biologically active molecules. During recent years, a great... (Review)
Review
Aziridine ring opening reactions have gained tremendous importance in the synthesis of nitrogen containing biologically active molecules. During recent years, a great effort has been put forward by scientists toward unique bond construction methodologies via ring opening of aziridines. In this regard, a wide range of chiral metal- and organo-catalyzed desymmetrization reactions of aziridines have been reported with carbon, sulfur, oxygen, nitrogen, halogen, and other nucleophiles. In this review, an outline of methodologies adopted by a number of scientists during 2013-2017 for aziridine ring opening reactions as well as their synthetic applications is described.
Topics: Aziridines; Stereoisomerism
PubMed: 29728870
DOI: 10.1007/s11030-018-9829-0 -
The Journal of Antibiotics Feb 2018A total synthesis of (+)-lysergic acid, which features the C-C bond formation between C10 and C11 via cleavage of an aziridine ring, was accomplished.
A total synthesis of (+)-lysergic acid, which features the C-C bond formation between C10 and C11 via cleavage of an aziridine ring, was accomplished.
Topics: Aziridines; Ergot Alkaloids; Indicators and Reagents; Lysergic Acid; Molecular Structure; Stereoisomerism
PubMed: 29375135
DOI: 10.1038/ja.2017.80 -
Metal Ion Complexes with Pyrazoles, Aziridines and Diaziridines - Synthesis and Biological Activity.Current Medicinal Chemistry 2019Heterocyclic compounds containing nitrogen ions, like pyrazoles, aziridines, diaziridines and their metal ion complexes with Cu(II), Zn(II) and Ru(III) and others... (Review)
Review
Heterocyclic compounds containing nitrogen ions, like pyrazoles, aziridines, diaziridines and their metal ion complexes with Cu(II), Zn(II) and Ru(III) and others exhibit a wide range of biological activity, including mainly anti-inflammatory, antioxidant, anticancer, and antimicrobial properties. Biological significance of these molecules and thus their potential use in medicine has driven growing interest into their coordination chemistry. A knowledge of the relationship between the structure of chemical compounds and their activity is needed for the synthesis of the preparations possessing the most beneficial features. The choice of interposed substituents may improve biocidal and antitumor action, reduce the toxicity of the initial substance, or even completely eliminate its adverse effects for healthy tissues. The main aim of this review paper is to present the current state of knowledge concerning the synthesis and biological activity of complexes with small heterocyclic ligands containing transition metal ions.
Topics: Anti-Infective Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antioxidants; Aziridines; Coordination Complexes; Drug Discovery; Humans; Ions; Ligands; Molecular Structure; Pyrazoles; Structure-Activity Relationship; Transition Elements
PubMed: 29473492
DOI: 10.2174/0929867325666180221124447 -
International Journal of Molecular... Dec 2021-Dimethylaziridine-2-carboxamides react with organolithium reagents yielding 2-aziridinylketones. The reaction with one equivalent of organolithium compound is selective...
-Dimethylaziridine-2-carboxamides react with organolithium reagents yielding 2-aziridinylketones. The reaction with one equivalent of organolithium compound is selective to amide carbonyl at a low (-78 °C) temperature. These ketones, in reaction with organolithium reagents, give symmetrical and unsymmetrical aziridinyl carbinols. The usage of excess phenyllithium may serve as a special N-Boc-protecting group cleavage method for acid-sensitive substrates.
Topics: Aziridines; Ketones; Lithium; Methanol; Molecular Structure; Organometallic Compounds; Stereoisomerism
PubMed: 34884949
DOI: 10.3390/ijms222313145 -
Nature Communications Jun 2022The activation of aziridines typically involves the use of strong Lewis acids or transition metals, and methods relying on weak interactions are rare. Herein, we report...
The activation of aziridines typically involves the use of strong Lewis acids or transition metals, and methods relying on weak interactions are rare. Herein, we report that cooperative chalcogen bonding interactions in confined sites can activate sulfonyl-protected aziridines. Among the several possible distinct bonding modes, our experiments and computational studies suggest that an activation mode involving the cooperative Se···O and Se···N interactions is in operation. The catalytic reactions between weakly bonded supramolecular species and nonactivated alkenes are considered as unfavorable approaches. However, here we show that the activation of aziridines by cooperative Se···O and Se···N interactions enables the cycloaddition of weakly bonded aziridine-selenide complex with nonactivated alkenes in a catalytic manner. Thus, weak interactions can indeed enable these transformations and are an alternative to methods relying on strong Lewis acids.
Topics: Alkenes; Aziridines; Chalcogens; Cycloaddition Reaction; Lewis Acids
PubMed: 35732663
DOI: 10.1038/s41467-022-31293-5 -
Blood Advances Jan 2024Allogeneic hematopoietic stem cell transplantation (HSCT) is highly effective for treating pediatric high-risk or relapsed acute lymphoblastic leukemia (ALL). For young...
Allogeneic hematopoietic stem cell transplantation (HSCT) is highly effective for treating pediatric high-risk or relapsed acute lymphoblastic leukemia (ALL). For young children, total body irradiation (TBI) is associated with severe late sequelae. In the FORUM study (NCT01949129), we assessed safety, event-free survival (EFS), and overall survival (OS) of 2 TBI-free conditioning regimens in children aged <4 years with ALL. Patients received fludarabine (Flu), thiotepa (Thio), and either busulfan (Bu) or treosulfan (Treo) before HSCT. From 2013 to 2021, 191 children received transplantation and were observed for ≥6 months (median follow-up: 3 years). The 3-year OS was 0.63 (95% confidence interval [95% CI], 0.52-0.72) and 0.76 (95% CI, 0.64-0.84) for Flu/Thio/Bu and Flu/Thio/Treo (P = .075), respectively. Three-year EFS was 0.52 (95% CI, 0.41-0.61) and 0.51 (95% CI, 0.39-0.62), respectively (P = .794). Cumulative incidence of nonrelapse mortality (NRM) and relapse at 3 years were 0.06 (95% CI, 0.02-0.12) vs 0.03 (95% CI: <0.01-0.09) (P = .406) and 0.42 (95% CI, 0.31-0.52) vs 0.45 (95% CI, 0.34-0.56) (P = .920), respectively. Grade >1 acute graft-versus-host disease (GVHD) occurred in 29% of patients receiving Flu/Thio/Bu and 17% of those receiving Flu/Thio/Treo (P = .049), whereas grade 3/4 occurred in 10% and 9%, respectively (P = .813). The 3-year incidence of chronic GVHD was 0.07 (95% CI, 0.03-0.13) vs 0.05 (95% CI, 0.02-0.11), respectively (P = .518). In conclusion, both chemotherapeutic conditioning regimens were well tolerated and NRM was low. However, relapse was the major cause of treatment failure. This trial was registered at www.clinicaltrials.gov as #NCT01949129.
Topics: Child; Child, Preschool; Humans; Busulfan; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Thiotepa; Transplantation Conditioning
PubMed: 37738088
DOI: 10.1182/bloodadvances.2023010591 -
Molecular Pharmaceutics Jun 2015
Topics: Aniline Compounds; Azo Compounds; Chemistry, Pharmaceutical; Chlorambucil; Dialysis; Fluorouracil; Immune Sera; Mercaptopurine; Methotrexate; Nitrogen Mustard Compounds; Research; Tetracycline; Thiotepa; Ultraviolet Rays; Uracil Mustard; gamma-Globulins
PubMed: 26027696
DOI: 10.1021/acs.molpharmaceut.5b00302