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Topics in Current Chemistry (Cham) Jan 2020The dramatic increase in atmospheric carbon dioxide (CO) concentrations has attracted human attention and many strategies about converting CO into high-value chemicals... (Review)
Review
The dramatic increase in atmospheric carbon dioxide (CO) concentrations has attracted human attention and many strategies about converting CO into high-value chemicals have been put forward. Metal-organic frameworks (MOFs), as a class of versatile materials, have been widely used in CO capture and chemical conversion, due to their unique porosity, multiple active centers and good stability and recyclability. Herein, we focused on the processes of chemical conversion of CO by MOFs-based catalysts, including the coupling reactions of epoxides, aziridines or alkyne molecules, CO hydrogenation, and other CO conversion reactions. The synthesized methods and high catalytic activity of MOFs-based materials were also analyzed systematically. Finally, a brief perspective on feasible strategies is presented to improve the catalytic activity of novel MOFs-based materials and explore the new CO conversion reactions.
Topics: Alkenes; Amines; Aziridines; Carbon Dioxide; Catalysis; Epoxy Compounds; Hydrogenation; Ionic Liquids; Metal-Organic Frameworks
PubMed: 31903506
DOI: 10.1007/s41061-019-0269-9 -
Pediatric Blood & Cancer Jun 2021Appropriate high-dose chemotherapy (HDC) for high-risk neuroblastoma has not yet been established. In Japan, a unique HDC regimen that comprises two cycles of a total of...
BACKGROUND
Appropriate high-dose chemotherapy (HDC) for high-risk neuroblastoma has not yet been established. In Japan, a unique HDC regimen that comprises two cycles of a total of 800 mg/m of thiotepa and a total of 280 mg/m of melphalan is widely utilized.
METHODS
To evaluate the safety and efficacy of this thiotepa-melphalan high-dose therapy for high-risk neuroblastoma, we reviewed the medical records of 41 patients with high-risk neuroblastoma who underwent this regimen followed by autologous peripheral blood stem cell rescue between 2002 and 2012. MYCN-amplified high-risk neuroblastomas were observed in 23 patients. All patients underwent intensive multidrug induction chemotherapy, but none underwent anti-GD2 antibody immunotherapy. The primary tumor was resected at the adequate time point.
RESULTS
The median follow-up duration for living patients was 9.2 years (range 5.5-14.0 years). The 5-year event-free survival (EFS) and overall survival from treatment initiation were 41.5 ± 7.7% and 56.1 ± 7.8%, respectively. The 5-year EFS of MYCN-amplified high-risk neuroblastoma patients was 60.9 ± 10.2%, which was significantly superior compared with those with MYCN-nonamplified high-risk neuroblastoma (16.7 ± 8.8%; p < .001). MYCN amplification was the most favorable prognostic factor for EFS (hazard ratio = 0.29; 95% confidence interval = 0.12-0.66). Of the 41 patients, three died because of regimen-related toxicity (infection, n = 2; microangiopathy, n = 1).
CONCLUSION
The thiotepa-melphalan high-dose therapy with thiotepa and melphalan may be effective for high-risk neuroblastoma. However, this regimen is toxic and warrants special attention in clinical practice.
Topics: Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Humans; Infant; Melphalan; N-Myc Proto-Oncogene Protein; Neuroblastoma; Thiotepa; Transplantation, Autologous
PubMed: 33788375
DOI: 10.1002/pbc.28896 -
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 -
ACS Chemical Biology Dec 2023GH127 and GH146 microorganismal retaining β-l-arabinofuranosidases, expressed by human gut microbiomes, feature an atypical catalytic domain and an unusual mechanism of...
GH127 and GH146 microorganismal retaining β-l-arabinofuranosidases, expressed by human gut microbiomes, feature an atypical catalytic domain and an unusual mechanism of action. We recently reported that both GH146 and HypBA1 are inhibited by β-l-furanosyl cyclophellitol epoxide, supporting the action of a zinc-coordinated cysteine as a catalytic nucleophile, where in most retaining GH families, an aspartate or glutamate is employed. This work presents a panel of β-l-furanosyl cyclophellitol epoxides and aziridines as mechanism-based GH146/HypBA1 inhibitors and activity-based probes. The β-l-furanosyl cyclophellitol aziridines both inhibit and label β-l-arabinofuranosidase efficiently (however with different activities), whereas the epoxide-derived probes favor GH146 over HypBA1. These findings are accompanied by X-ray structural analysis of the unmodified β-l-furanosyl cyclophellitol aziridine in complex with both isozymes, which were shown to react by nucleophilic opening of the aziridine, at the pseudoanomeric carbon, by the active site cysteine nucleophile to form a stable thioether bond. Altogether, our activity-based probes may serve as chemical tools for the detection and identification of low-abundance β-l-arabinofuranosidases in complex biological samples.
Topics: Humans; Cysteine; Glycoside Hydrolases; Aziridines; Epoxy Compounds
PubMed: 38051515
DOI: 10.1021/acschembio.3c00558 -
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 -
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 -
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 -
Journal of Natural Medicines Jan 2024Epoxides, aziridines, and cyclopropanes are found in various medicinal natural products, including polyketides, terpenes, peptides, and alkaloids. Many classes of... (Review)
Review
Epoxides, aziridines, and cyclopropanes are found in various medicinal natural products, including polyketides, terpenes, peptides, and alkaloids. Many classes of biosynthetic enzymes are involved in constructing these ring structures during their biosynthesis. This review summarizes our current knowledge regarding how α-ketoglutarate-dependent nonheme iron enzymes catalyze the formation of epoxides, aziridines, and cyclopropanes in nature, with a focus on enzyme mechanisms.
Topics: Iron; Ketoglutaric Acids; Catalysis; Cyclopropanes; Aziridines; Epoxy Compounds
PubMed: 37980694
DOI: 10.1007/s11418-023-01760-4 -
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