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Molecules (Basel, Switzerland) Oct 2022Multi-substituted pyrroles are synthesized from regiospecific aziridine ring-opening and subsequent intramolecular cyclization with a carbonyl group at the -position in...
Multi-substituted pyrroles are synthesized from regiospecific aziridine ring-opening and subsequent intramolecular cyclization with a carbonyl group at the -position in the presence of Lewis acid or protic acid. This method is highly atom economical where all the atoms of the reactants are incorporated into the final product with the removal of water. This new protocol is applied to the synthesis of various pyrroles, including natural products.
Topics: Pyrroles; Lewis Acids; Aziridines; Biological Products; Water
PubMed: 36296466
DOI: 10.3390/molecules27206869 -
Angewandte Chemie (International Ed. in... Feb 2023The development of preparative methods for the synthesis of four-membered carbocycles is gaining increasing importance due to the widespread utility of cyclic compounds...
The development of preparative methods for the synthesis of four-membered carbocycles is gaining increasing importance due to the widespread utility of cyclic compounds in medicinal chemistry. Herein, we report the development of a new methodology for the production of spirocyclic epoxides and aziridines containing a cyclobutane motif. In a two-step one-pot process, a bicyclo[1.1.0]butyl sulfoxide is lithiated and added to a ketone, aldehyde or imine, and the resulting intermediate is cross-coupled with an aryl triflate through C-C σ-bond alkoxy- or aminopalladation with concomitant epoxide or aziridine formation. After careful optimization, a remarkably efficient reaction was conceived that tolerated a broad variety of both aromatic and aliphatic substrates. Lastly, through several high yielding ring-opening reactions, we demonstrated the excellent applicability of the products as modular building blocks for the introduction of three-dimensional structures into target molecules.
PubMed: 36507714
DOI: 10.1002/anie.202217064 -
Journal of the American Chemical Society Mar 2020Identifying and characterizing the enzymes responsible for an observed activity within a complex eukaryotic catabolic system remains one of the most significant...
Identifying and characterizing the enzymes responsible for an observed activity within a complex eukaryotic catabolic system remains one of the most significant challenges in the study of biomass-degrading systems. The debranching of both complex hemicellulosic and pectinaceous polysaccharides requires the production of α-l-arabinofuranosidases among a wide variety of coexpressed carbohydrate-active enzymes. To selectively detect and identify α-l-arabinofuranosidases produced by fungi grown on complex biomass, potential covalent inhibitors and probes which mimic α-l-arabinofuranosides were sought. The conformational free energy landscapes of free α-l-arabinofuranose and several rationally designed covalent α-l-arabinofuranosidase inhibitors were analyzed. A synthetic route to these inhibitors was subsequently developed based on a key Wittig-Still rearrangement. Through a combination of kinetic measurements, intact mass spectrometry, and structural experiments, the designed inhibitors were shown to efficiently label the catalytic nucleophiles of retaining GH51 and GH54 α-l-arabinofuranosidases. Activity-based probes elaborated from an inhibitor with an aziridine warhead were applied to the identification and characterization of α-l-arabinofuranosidases within the secretome of grown on arabinan. This method was extended to the detection and identification of α-l-arabinofuranosidases produced by eight biomass-degrading basidiomycete fungi grown on complex biomass. The broad applicability of the cyclophellitol-derived activity-based probes and inhibitors presented here make them a valuable new tool in the characterization of complex eukaryotic carbohydrate-degrading systems and in the high-throughput discovery of α-l-arabinofuranosidases.
Topics: Aziridines; Basidiomycota; Cyclopentanes; Enzyme Inhibitors; Fungal Proteins; Glycoside Hydrolases; Kinetics; Thermodynamics
PubMed: 32053363
DOI: 10.1021/jacs.9b11351 -
PloS One 2015Senescence is a terminal growth arrest that functions as a tumor suppressor in aging and precancerous cells and is a response to selected anticancer compounds....
PURPOSE
Senescence is a terminal growth arrest that functions as a tumor suppressor in aging and precancerous cells and is a response to selected anticancer compounds. Lysosomal-β-galactosidase (GLB1) hydrolyzes β-galactose from glycoconjugates and is the origin of senescence-associated β-gal activity (SA-β-gal). Using a new GLB1 antibody, senescence biology was investigated in prostate cancer (PCa) tissues.
EXPERIMENTAL DESIGN
In vitro characterization of GLB1 was determined in primary prostate epithelial cell cultures passaged to replicative senescence and in therapy-induced senescence in PCa lines using chemotherapeutic agents. FFPE tissue microarrays were subjected to immunofluorescent staining for GLB1, Ki67 and HP1γ and automated quantitative imaging initially using AQUA in exploratory samples and Vectra in a validation series.
RESULTS
GLB1 expression accumulates in replicative and induced senescence and correlates with senescent morphology and P16 (CDKN2) expression. In tissue arrays, quantitative imaging detects increased GLB1 expression in high-grade prostatic intraepithelial neoplasia (HGPIN), known to contain senescent cells, and cancer compared to benign prostate tissues (p<0.01) and senescent cells contain low Ki67 and elevated HP1γ. Within primary tumors, elevated GLB1 associates with lower T stage (p=0.01), localized versus metastatic disease (p=0.0003) and improved PSA-free survival (p=0.03). Increased GLB1 stratifies better PSA-free survival in intermediate grade PCa (0.01). Tissues that elaborate higher GLB1 display increased uniformity of expression.
CONCLUSION
Increased GLB1 is a valuable marker in formalin-fixed paraffin-embedded (FFPE) tissues for the senescence-like phenotype and associates with improved cancer outcomes. This protein addresses a lack of senescence markers and should be applicable to study the biologic role of senescence in other cancers.
Topics: Aged; Antineoplastic Agents; Aziridines; Benzoquinones; Biomarkers; Cellular Senescence; Epithelial Cells; Formaldehyde; Gene Expression Regulation, Neoplastic; Humans; Kallikreins; Male; Middle Aged; Neoplasm Grading; Neoplasm Recurrence, Local; Neoplasm Staging; Paraffin Embedding; Primary Cell Culture; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Signal Transduction; Survival Analysis; Tissue Fixation; beta-Galactosidase
PubMed: 25876105
DOI: 10.1371/journal.pone.0124366 -
Journal of the American Chemical Society Apr 2020A photoassisted Ni-catalyzed reductive cross-coupling between tosyl-protected alkyl aziridines and commercially available (hetero)aryl iodides is reported. This mild and...
A photoassisted Ni-catalyzed reductive cross-coupling between tosyl-protected alkyl aziridines and commercially available (hetero)aryl iodides is reported. This mild and modular method proceeds in the absence of stoichiometric heterogeneous reductants and uses an inexpensive organic photocatalyst to access medicinally valuable β-phenethylamine derivatives. Unprecedented reactivity was achieved with the activation of cyclic aziridines. Mechanistic studies suggest that the regioselectivity and reactivity observed under these conditions are a result of nucleophilic iodide ring opening of the aziridine to generate an iodoamine as the active electrophile. This strategy also enables cross-coupling with Boc-protected aziridines.
Topics: Aziridines; Catalysis; Humans; Iodides; Molecular Structure; Phenethylamines; Stereoisomerism
PubMed: 32250602
DOI: 10.1021/jacs.0c01724 -
Organic Letters Aug 2022We present a unique strategy for the synthesis of vicinal amino alcohols. Ring opening of aziridines with pendant silanols is compatible with a range of substrates. To...
Ring Opening of Aziridines by Pendant Silanols Allows for Preparations of (±)-Clavaminol H, (±)-Des-Acetyl-Clavaminol H, (±)-Dihydrosphingosine, and (±)--Hexanoyldihydrosphingosine.
We present a unique strategy for the synthesis of vicinal amino alcohols. Ring opening of aziridines with pendant silanols is compatible with a range of substrates. To engage productively in ring opening, the aziridine must be at least mildly activated, and a variety of such -substituents are tolerated. The utility of this methodology is highlighted in facile preparations of the natural products (±)-Clavaminol H, (±)-dihydrosphingosine, and (±)--hexanoyldihydrosphingosine as well as a natural product analogue (±)-des-acetyl-Clavaminol H.
Topics: Aziridines; Ceramides; Molecular Structure; Silanes; Sphingosine; Stereoisomerism
PubMed: 35951966
DOI: 10.1021/acs.orglett.2c02496 -
Molecules (Basel, Switzerland) Oct 2018Oxaziridines have emerged as powerful and elegant oxygen- and nitrogen-transfer agents for a broad array of nucleophiles, due to the remarkably high and tunable... (Review)
Review
Oxaziridines have emerged as powerful and elegant oxygen- and nitrogen-transfer agents for a broad array of nucleophiles, due to the remarkably high and tunable reactivities. However, the asymmetric catalysis involving oxaziridines is still in its infancy. Herein, this review aims to examine recent advances in the catalytic asymmetric transformations of oxaziridines, including oxidation, amination, cycloaddition and deracemization.
Topics: Amination; Aziridines; Catalysis; Cycloaddition Reaction; Molecular Structure
PubMed: 30332802
DOI: 10.3390/molecules23102656 -
The Journal of Organic Chemistry Dec 2021Boroxinate complexes of VAPOL and VANOL are a chiral anionic platform that can serve as a versatile staging arena for asymmetric catalysis. The structural underpinning...
Boroxinate complexes of VAPOL and VANOL are a chiral anionic platform that can serve as a versatile staging arena for asymmetric catalysis. The structural underpinning of the platform is a chiral polyborate core that covalently links together alcohols (or phenols) and vaulted biaryl ligands. The polyborate platform is assembled in situ by the substrate of the reaction, and thus a multiplex of chiral catalysts can be rapidly assembled from various alcohols (or phenols) and bis-phenol ligands for screening of catalyst activity. In the present study, variations in the steric and electronic properties of the phenol/alcohol component of the boroxinate catalyst are probed to reveal their effects on the asymmetric induction in the catalytic asymmetric aziridination reaction. A Hammett study is consistent with a mechanism in which the two substrates are hydrogen-bonded to the boroxinate core in the enantiogenic step. The results of the Hammett study are supported by a computational study in which it is found that the H-O distance of the protonated imine hydrogen bonded to the anionic boroxinate core decreases with an increase in the electron releasing ability of the phenol unit incorporated into the boroxinate. The results are not consistent with a mechanism in which the boroxinate catalyst functions as a Lewis acid and activates the imine by a Lewis acid/Lewis base interaction.
Topics: Anions; Aziridines; Catalysis; Electronics; Stereoisomerism
PubMed: 34852456
DOI: 10.1021/acs.joc.1c01769 -
Clinical Lymphoma, Myeloma & Leukemia Jul 2020High-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) has been investigated in patients with primary central nervous system lymphoma (PCNSL) and...
Durable Survival Outcomes in Primary and Secondary Central Nervous System Lymphoma After High-dose Chemotherapy and Autologous Stem Cell Transplantation Using a Thiotepa, Busulfan, and Cyclophosphamide Conditioning Regimen.
BACKGROUND
High-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) has been investigated in patients with primary central nervous system lymphoma (PCNSL) and non-Hodgkin lymphoma (NHL) with CNS involvement and has shown promising results.
PATIENTS AND METHODS
A retrospective analysis was performed of 48 consecutive patients who had undergone HDC/ASCT with TBC (thiotepa, busulfan, cyclophosphamide) conditioning for PCNSL (27 patients), secondary CNS lymphoma (SCNSL) (8 patients), or relapsed disease with CNS involvement (13 patients) from July 2006 to December 2017. Of the 27 patients with PCNSL, 21 had undergone ASCT at first complete remission (CR1).
RESULTS
The 2-year progression-free survival (PFS) rate was 80.5% (95% confidence interval [CI], 69.9-92.9) and the 2-year overall survival (OS) rate was 80.1% (95% CI, 69.2%-92.7%) among all patients. The 2-year PFS and OS rate for patients with PCNSL in CR1 was 95.2% (95% CI, 86.6%-100%) and 95.2% (95% CI, 86.6%-100%), respectively. On univariate analysis of the patients with PCNSL, ASCT in CR1 was the only variable statistically significant for outcome (P = .007 for PFS; P = .008 for OS). Among patients with SCNSL or CNS relapse, the 2-year PFS and OS rate were comparable at 75.9% (95% CI, 59.5%-96.8%) and 75.3% (95% CI, 58.6%-98.6%), respectively. The most common side effects were febrile neutropenia (89.6%; of which 66.7% had an infectious etiology identified), nausea/vomiting (85.4%), diarrhea (93.8%), mucositis (89.6%), and electrolyte abnormalities (89.6%). Four patients (8.3%) died of treatment-related overwhelming infection; of these patients, 3 had SCNSL.
CONCLUSION
HDC and ASCT using TBC conditioning for both PCNSL and secondary CNS NHL appears to have encouraging long-term efficacy with manageable side effects.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Central Nervous System Neoplasms; Cyclophosphamide; Disease-Free Survival; Female; Humans; Lymphoma; Male; Middle Aged; Retrospective Studies; Thiotepa
PubMed: 32229199
DOI: 10.1016/j.clml.2020.02.009 -
Proceedings of the Royal Society of... Aug 1963
Topics: Chlorambucil; Cyclophosphamide; Genetic Diseases, X-Linked; Hodgkin Disease; Humans; Leukemia, Hairy Cell; Lymphatic Diseases; Melphalan; Nitrogen Mustard Compounds; Peptide Nucleic Acids; Prednisolone; Prednisone; Severe Combined Immunodeficiency; Thiotepa
PubMed: 14052445
DOI: No ID Found