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Molecules (Basel, Switzerland) Jul 2023The efficient one-pot halofluorination of a -enaminophosphonate/-iminophosphonate tautomeric mixture resulting in ,-halofluorinated -iminophosphonates is reported....
The efficient one-pot halofluorination of a -enaminophosphonate/-iminophosphonate tautomeric mixture resulting in ,-halofluorinated -iminophosphonates is reported. Subsequent imine reduction gave the corresponding -aminophosphonates as a racemic mixture or with high diastereoselectivity. The proposed protocol is the first example of a synthesis of -inactivated aziridines substituted by a fluorine and phosphonate moiety on the same carbon atom. Based on spectroscopic and theoretical studies, we determined the / geometry of the resulting fluorinated aziridine-2-phosphonate. Our procedure, involving the reduction of -fluoroaziridine mixture , allows us to isolate chiral aziridines as well as aziridines that do not contain a fluorine atom. We also investigated the influence of the fluorine atom on the reactivity of aziridine through an acid-catalyzed regioselective ring-opening reaction. The results of DFT calculations, at the PCM/ωB97x-D/def2-TZVPD level of theory, are in good agreement with the experiments. The transition states of the S2 intramolecular cyclization of vicinal haloamines have been modeled.
PubMed: 37513451
DOI: 10.3390/molecules28145579 -
Organic Letters Sep 2023A nickel-catalyzed reductive cross-coupling of aziridines and allylic chlorides was realized by using manganese metal as the reducing agent. This protocol afforded a...
A nickel-catalyzed reductive cross-coupling of aziridines and allylic chlorides was realized by using manganese metal as the reducing agent. This protocol afforded a convenient approach to obtain β-allyl-substituted arylethylamines bearing various functional groups. The utility of this reaction was also demonstrated by scale-up preparation and diverse transformations, including the synthesis of Baclofen and several bioactive molecular motifs.
PubMed: 37642345
DOI: 10.1021/acs.orglett.3c02399 -
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 -
Bone Marrow Transplantation Nov 2023Thiotepa/carmustine (TT-BCNU) is a commonly used autologous transplant (ASCT) conditioning regimen for primary DLBCL of the CNS (PCNSL). The total thiotepa dose varies...
Impact of thiotepa dose-intensity in primary diffuse large B-cell lymphoma of the central nervous system undergoing autologous hematopoietic cell transplant with thiotepa/carmustine conditioning.
Thiotepa/carmustine (TT-BCNU) is a commonly used autologous transplant (ASCT) conditioning regimen for primary DLBCL of the CNS (PCNSL). The total thiotepa dose varies among TT-BCNU recipients, with some centers administering a total dose of 20 mg/kg, while others using 10 mg/kg. We retrospectively assessed the impact of thiotepa dose intensity on ASCT outcomes in 218 adult PCNSL patients who underwent a first ASCT with TT-BCNU conditioning and received either a total thiotepa dose of 10 mg/kg (TT-10 group; N = 90), or 20 mg/kg (TT-20 group; N = 128). The median follow-up of survivors was 22 months. The cumulative incidence of 1-year non-relapse mortality (NRM) for TT-10 and TT-20 cohorts were 6% (95%CI = 2-12%) vs. 4% (95%CI = 1-8%), respectively (p = 0.66). The 3-year cumulative incidence of relapse (15% vs. 13%; p = 0.67), progression-free survival (PFS) (71% vs. 80%; p = 0.25) and overall survival (OS) (79% vs. 83%; p = 0.56) were similar in the TT-10 and TT-20 groups, respectively. On multivariate analysis compared to TT-10, the TT-20 cohort was not associated with significantly different risk of NRM (Hazard ration [HR] = 0.77; p = 0.64), relapse/progression (HR = 0.87; p = 0.74), PFS (HR = 0.80; p = 0.48) or OS (HR = 1.10; p = 0.80). In conclusion thiotepa dose-intensity in TT-BCNU conditioning does not impact ASCT outcomes of PCNSL patients.
Topics: Adult; Humans; Thiotepa; Carmustine; Autografts; Hematopoietic Stem Cell Transplantation; Retrospective Studies; Central Nervous System Neoplasms; Neoplasm Recurrence, Local; Transplantation, Autologous; Central Nervous System; Lymphoma, Large B-Cell, Diffuse; Recurrence; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37563283
DOI: 10.1038/s41409-023-02071-8 -
Frontiers in Chemistry 2023Herein we report a copper-catalyzed synthesis of imidazolidine by employing the reaction of aziridine with imine. The reaction smoothly provided a diverse range of...
Herein we report a copper-catalyzed synthesis of imidazolidine by employing the reaction of aziridine with imine. The reaction smoothly provided a diverse range of 2-substituted imidazolidines with high compatibility with various functional groups. Moreover, during our investigation, we discovered that isocyanate also reacted with aziridine to yield substituted imidazolidinones efficiently. The versatility of these reactions was further demonstrated by their application in the synthesis of hybrid molecules derived from two pharmaceutical compounds. This approach opens new possibilities for the discovery of novel classes of bioactive molecules.
PubMed: 37841205
DOI: 10.3389/fchem.2023.1272034 -
Journal of Pharmaceutical and... Sep 2023Roxadustat is the first drug approved for anemia due to chronic kidney disease. Drug degradation profile is very crucial for assessing the quality and safety of the drug...
Roxadustat is the first drug approved for anemia due to chronic kidney disease. Drug degradation profile is very crucial for assessing the quality and safety of the drug substances and their formulations. Forced degradation studies are conducted for quick prediction of drug degradation products. Forced degradation of roxadustat was carried out as per ICH guidelines, and nine degradation products (DPs) were observed. These DPs (DP-1 to DP-9) were separated using the reverse phase HPLC gradient method with an XBridge column (250 mm × 4.6 mm, 5 µm). The mobile phase consisted of 0.1% formic acid (solvent A) and acetonitrile (solvent B) at a flow rate of 1.0 ml/min. The chemical structures of all the DPs were proposed by using LC-Q-TOF/MS. DP-4 and DP-5, the two major degradation impurities, were isolated, and NMR was used to confirm their chemical structures. Based on our experiments, the roxadustat was found stable to thermal degradation in solid state and oxidative conditions. However, it was unstable in acidic, basic, and photolytic conditions. A very remarkable observation was made about DP-4 impurity. DP-4 was generated as a common degradation impurity in alkaline hydrolysis, neutral hydrolysis as well as photolysis conditions. DP-4 has a similar molecular mass to roxadustat but is structurally different. DP-4 is chemically, (1a-methyl-6-oxo-3-phenoxy-1,1a,6,6a-tetrahydroindeno [1,2-b] aziridine-6a-carbonyl) glycine. In silico toxicity study was conducted using Dereck software to gain the best knowledge of the drug and its degradation products towards carcinogenicity, mutagenicity, teratogenicity, and skin sensitivity. A further study using molecular docking confirmed the potential interaction of DPs with proteins responsible for toxicity. DP-4 shows a toxicity alert due to the presence of aziridine moiety.
Topics: Tandem Mass Spectrometry; Molecular Docking Simulation; Drug Stability; Chromatography, High Pressure Liquid; Solvents; Glycine; Hydrolysis; Oxidation-Reduction; Photolysis
PubMed: 37320975
DOI: 10.1016/j.jpba.2023.115517 -
Angewandte Chemie (International Ed. in... Nov 2023Azomethine ylides are typically in situ generated synthons for making N-heterocycles through cycloaddition reactions. But an offbeat aspect about them is the isomeric...
Azomethine ylides are typically in situ generated synthons for making N-heterocycles through cycloaddition reactions. But an offbeat aspect about them is the isomeric nature of aldiminium-based azomethine ylides and (alkyl/aryl)(amino)carbenes, interconvertible by a formal 1,3-H transfer. Herein, two thermally robust azomethine ylides with a N-appended picolyl sidearm are isolated, which cyclize to aziridines at 80 °C but unprecedentedly result CAAC-CuCl (CAAC=cyclic(alkyl)(amino)carbene) complexes when heated with CuCl at merely 60 °C. The pendant N , as revealed by computational analysis, plays a crucial role in this unusual 1,3-H shift using a deprotonation-protonation sequence, as well as in placing the CuCl at the carbenic site in tandem. The softer nature of Cu is also critical. Chelating CAACs are rare and one with a N-tethered additional donor is priorly unknown. Both CAAC and aziridine are bidentate chelators giving highly active cationic Rh catalysts for hydrosilylating unactivated olefins by Et SiH. Notably, the aziridine-Rh is superior than the CAAC-Rh catalyst.
PubMed: 37758683
DOI: 10.1002/anie.202312858 -
Transplantation and Cellular Therapy Aug 2023Autologous stem cell transplantation (ASCT) remains a cornerstone in the treatment of both Hodgkin lymphoma (HL) and various non-Hodgkin lymphoma (NHL) subtypes. BEAM...
Autologous stem cell transplantation (ASCT) remains a cornerstone in the treatment of both Hodgkin lymphoma (HL) and various non-Hodgkin lymphoma (NHL) subtypes. BEAM (carmustine, etoposide, cytarabine, and melphalan) is the most frequently used conditioning regimen; however, owing due to limited availability and toxicity of carmustine, thiotepa-containing regimens have been suggested. We previously reported encouraging results in ASCT with a TECAM (thiotepa, etoposide, cyclophosphamide, cytarabine, and melphalan) conditioning regimen from 2000 to 2013. We aimed to update our experience with the TECAM regimen by adding our experience from 2013 to 2020 to the previously reported cohort. Moreover, we aimed to use the detailed data for the 2 transplant cohorts to identify improvements in ASCT outcomes in the recent era. We retrospectively analyzed all lymphoma patients who underwent ASCT at our center between January 2000 and December 2020. A total of 353 lymphoma patients were included (142 in the newer cohort added to 211 previously reported patients), all of whom were treated with our standard TECAM conditioning regimen. The cohort included 127 patients with HL, 107 with DLBCL, and 119 with other NHL subtypes. The newer cohort was characterized by significantly poorer Eastern Cooperative Oncology Group Performance Status (ECOG-PS) prior to ASCT (45.7% versus 19.3% with ECOG-PS ≥1; P < .01), whereas a higher proportion of patients entered transplantation in complete response (CR) (71.9% versus 47.8%; P < .01). The median follow-up after ASCT was 136.4 months (95% confidence interval [CI], 91.4 to 181.4 months). The 3-year progression-free survival (PFS) and overall survival (OS) rates post-ASCT for the entire cohort were 59.8% and 79.3%, respectively. Evaluating the 303 of 353 patients (86.4%) who entered ASCT with a responsive disease-a population that represents today's approach to the selection of patients for ASCT-the 3-year PFS and OS rates were 61.5% and 81.9%, respectively. In this population, the 3-year PFS rate was 62.2% for HL, 62.6% for DLBCL, 64.3% for primary central nervous system lymphoma (PCNSL), and the 3-year OS rate were 90.1%, 75.2%, and 78.6%, respectively. OS was significantly better in the newer cohort (P < .01), but not when evaluating only patients who entered ASCT with responsive disease. Dose reductions, poor disease status, and poor ECOG-PS at ASCT entry were associated with worse outcomes across all lymphoma subtypes. In accordance with our previous report, patients entering transplantation for DLBCL with a partial response achieved similar outcomes as those with a CR. Eighteen patients died within the first 100 days, 8 due to disease progression and 10 due to transplantation-related complications (2.8%). There were no cases of interstitial pneumonitis syndrome. Twenty-two cases (6.2%) of secondary malignancies were documented. Our results confirm that TECAM is an effective and safe conditioning regimen for ASCT in patients with HL and various NHLs, including favorable results in PCNSL. Despite a higher proportion of frail patients, the newer cohort's outcomes were favorable, driven by better lymphoma control pretransplantation. In the DLBCL cohort, ECOG-PS had more prognostic value than achieving a CR pre-ASCT, a finding relevant to the optimal allocation of patients to different treatment options in the era of chimeric antigen receptor T cell availability.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Etoposide; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Lymphoma; Lymphoma, Non-Hodgkin; Melphalan; Retrospective Studies; Thiotepa; Transplantation, Autologous
PubMed: 37160229
DOI: 10.1016/j.jtct.2023.04.022 -
Chemical Science Oct 2023Despite the myriad Cu-catalyzed nitrene transfer methodologies to form new C-N bonds (, amination, aziridination), the critical reaction intermediates have largely...
Despite the myriad Cu-catalyzed nitrene transfer methodologies to form new C-N bonds (, amination, aziridination), the critical reaction intermediates have largely eluded direct characterization due to their inherent reactivity. Herein, we report the synthesis of dipyrrin-supported Cu nitrenoid adducts, investigate their spectroscopic features, and probe their nitrene transfer chemistry through detailed mechanistic analyses. Treatment of the dipyrrin Cu complexes with substituted organoazides affords terminally ligated organoazide adducts with minimal activation of the azide unit as evidenced by vibrational spectroscopy and single crystal X-ray diffraction. The Cu nitrenoid, with an electronic structure most consistent with a triplet nitrene adduct of Cu, is accessed following geometric rearrangement of the azide adduct from κ-N terminal ligation to κ-N internal ligation with subsequent expulsion of N. For perfluorinated arylazides, stoichiometric and catalytic C-H amination and aziridination was observed. Mechanistic analysis employing substrate competition reveals an enthalpically-controlled, electrophilic nitrene transfer for primary and secondary C-H bonds. Kinetic analyses for catalytic amination using tetrahydrofuran as a model substrate reveal pseudo-first order kinetics under relevant amination conditions with a first-order dependence on both Cu and organoazide. Activation parameters determined from Eyring analysis (Δ = 9.2(2) kcal mol, Δ = -42(2) cal mol K, Δ = 21.7(2) kcal mol) and parallel kinetic isotope effect measurements (1.10(2)) are consistent with rate-limiting Cu nitrenoid formation, followed by a proposed stepwise hydrogen-atom abstraction and rapid radical recombination to furnish the resulting C-N bond. The proposed mechanism and experimental analysis are further corroborated by density functional theory calculations. Multiconfigurational calculations provide insight into the electronic structure of the catalytically relevant Cu nitrene intermediates. The findings presented herein will assist in the development of future methodology for Cu-mediated C-N bond forming catalysis.
PubMed: 37829016
DOI: 10.1039/d3sc03641c -
Chemical Science Nov 2023The introduction of nitrogen atoms into small molecules is of fundamental importance and it is vital that ever more efficient and selective methods for achieving this... (Review)
Review
The introduction of nitrogen atoms into small molecules is of fundamental importance and it is vital that ever more efficient and selective methods for achieving this are developed. With this aim, the potential of nitrene chemistry has long been appreciated but its application has been constrained by the extreme reactivity of these labile species. This liability however can be attenuated by complexation with a transition metal and the resulting metal nitrenoids have unique and highly versatile reactivity which includes the amination of certain types of aliphatic C-H bonds as well as reactions with alkenes to afford aziridines. At least one new chiral centre is typically formed in these processes and the development of catalysts to exert control over enantioselectivity in nitrenoid-mediated amination has become a growing area of research, particularly over the past two decades. Compared with some synthetic methods, metal nitrenoid chemistry is notable in that chemists can draw from a diverse array of metals and catalysts , ranging from metal-ligand complexes, bearing a variety of ligand types, bio-inspired metalloporphyrins, all the way through to, very recently, engineered enzymes themselves. In the latter category in particular, rapid progress is being made, the rate of which suggests that this approach may be instrumental in addressing some of the outstanding challenges in the field. This review covers key developments and strategies that have shaped the field, in addition to the latest advances, up until September 2023.
PubMed: 38020383
DOI: 10.1039/d3sc04661c