-
Journal of the American Chemical Society Nov 2022Aziridines are readily available C(sp) precursors that afford valuable β-functionalized amines upon ring opening. In this article, we report a Ni/photoredox methodology...
Aziridines are readily available C(sp) precursors that afford valuable β-functionalized amines upon ring opening. In this article, we report a Ni/photoredox methodology for C(sp)-C(sp) cross-coupling between aziridines and methyl/1°/2° aliphatic alcohols activated as benzaldehyde dialkyl acetals. Orthogonal activation modes of each alkyl coupling partner facilitate cross-selectivity in the C(sp)-C(sp) bond-forming reaction: the benzaldehyde dialkyl acetal is activated via hydrogen atom abstraction and β-scission via a bromine radical (generated in situ from single-electron oxidation of bromide), whereas the aziridine is activated at the Ni center via reduction. We demonstrate that an Ni(II) azametallacycle, conventionally proposed in aziridine cross-coupling, is not an intermediate in the productive cross-coupling. Rather, stoichiometric organometallic and linear free energy relationship studies indicate that aziridine activation proceeds via Ni(I) oxidative addition, a previously unexplored elementary step.
Topics: Acetals; Catalysis; Benzaldehydes; Nickel; Aziridines
PubMed: 36256882
DOI: 10.1021/jacs.2c09294 -
Chemistry (Weinheim An Der Bergstrasse,... Jan 2023The protonation of commercially available porphyrin ligands yields a class of bifunctional catalysts able to promote the synthesis of N-alkyl oxazolidinones by CO...
The protonation of commercially available porphyrin ligands yields a class of bifunctional catalysts able to promote the synthesis of N-alkyl oxazolidinones by CO cycloaddition to corresponding aziridines. The catalytic system does not require the presence of any Lewis base or additive, and shows interesting features both in terms of cost effectiveness and eco-compatibility. The metal-free methodology is active even with a low catalytic loading of 1 % mol, and the chemical stability of the protonated porphyrin allowed it to be recycled three times without any decrease in performance. In addition, a DFT study was performed in order to suggest how a simple protonated porphyrin can mediate CO cycloaddition to aziridines to yield oxazolidinones.
Topics: Porphyrins; Carbon Dioxide; Oxazolidinones; Metals; Aziridines
PubMed: 36194105
DOI: 10.1002/chem.202202729 -
Cellular Physiology and Biochemistry :... Sep 2022The development of new nanomaterials has been growing in recent decades to bring benefits in several areas, especially carbon-based nanoparticles, which have unique...
BACKGROUND/AIMS
The development of new nanomaterials has been growing in recent decades to bring benefits in several areas, especially carbon-based nanoparticles, which have unique physical-chemical properties and allow to take on several applications. Consequently, the use of new nanomaterials without previous toxicological studies raises concern about possible harmful health effects. The aim of this study was to investigate the cytotoxic profile of a new multi-walled carbon nanotube (MWCNT) functionalized with tetraethylenepentamine called OCNT-TEPA using in vitro assays in murine macrophage cells linage J774 A.1.
METHODS
OCNT-TEPA was characterized by transmission electron microscopy (TEM) and high resolution TEM (HR-TEM), scanning electron microscopy (SEM), zeta potential and dynamic light scattering (DLS), and its cytotoxic effects were evaluated at 24 and 48 hours by cell viability assays (MTT and NR), morphology and cell recovery (optic microscopy and clonogenic assay), formation of reactive oxygen (ROS) and nitric oxide (NO) species, inflammatory profile (IL-6 and TNF cytokines), mitochondrial membrane potential analysis (MMP), activation of the caspase 3 pathway and cell death (flow cytometry).
RESULTS
The data showed a significant decrease in cell viability, increased production of ROS and NO, alteration of mitochondrial membrane potential, increased levels of inflammatory cytokines, alteration of cell morphology, activation of the Caspase 3 pathway and consequently cell death, in the highest concentrations of OCNT-TEPA tested in the periods of 24 and 48 hours.
CONCLUSION
The analyses showed that OCNT-TEPA has a dose-dependent cytotoxic profile, which may be harmful to murine macrophages (J774 A.1) and may represent a health risk.
Topics: Animals; Antineoplastic Agents; Caspase 3; Cell Survival; Cytokines; Interleukin-6; Macrophages; Mice; Nanotubes, Carbon; Nitric Oxide; Oxygen; Reactive Oxygen Species; Triethylenephosphoramide
PubMed: 36168820
DOI: 10.33594/000000573 -
Molecules (Basel, Switzerland) Sep 2022Treatment of Mn(N(SiMe))(THF) with bulky chelating bis(alkoxide) ligand [1,1':4',1''-terphenyl]-2,2''-diylbis(diphenylmethanol) (H[O-terphenyl-O]) formed a seesaw...
Treatment of Mn(N(SiMe))(THF) with bulky chelating bis(alkoxide) ligand [1,1':4',1''-terphenyl]-2,2''-diylbis(diphenylmethanol) (H[O-terphenyl-O]) formed a seesaw manganese(II) complex Mn[O-terphenyl-O](THF), characterized by structural, spectroscopic, magnetic, and analytical methods. The reactivity of Mn[O-terphenyl-O](THF) with various nitrene precursors was investigated. No reaction was observed between Mn[O-terphenyl-O](THF) and aryl azides. In contrast, the treatment of Mn[O-terphenyl-O](THF) with iminoiodinane PhINTs (Ts = toluenesulfonyl) was consistent with the formation of a metal-nitrene complex. In the presence of styrene, the reaction led to the formation of aziridine. Combining varying ratios of styrene and PhINTs in different solvents with 10 mol% of Mn[O-terphenyl-O](THF) at room temperature produced 2-phenylaziridine in up to a 79% yield. Exploration of the reactivity of Mn[O-terphenyl-O](THF) with various olefins revealed (1) moderate aziridination yields for -substituted styrenes, irrespective of the electronic nature of the substituent; (2) moderate yield for 1,1'-disubstituted α-methylstyrene; (3) no aziridination for aliphatic α-olefins; (4) complex product mixtures for the β-substituted styrenes. DFT calculations suggest that iminoiodinane is oxidatively added upon binding to Mn, and the resulting formal imido intermediate has a high-spin Mn(III) center antiferromagnetically coupled to an imidyl radical. This imidyl radical reacts with styrene to form a sextet intermediate that readily reductively eliminates the formation of a sextet Mn(II) aziridine complex.
PubMed: 36144492
DOI: 10.3390/molecules27185751 -
BMC Cancer Sep 2022Primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (PCNSL) is a rare disorder with an increasing incidence over the past decades. High-level... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (PCNSL) is a rare disorder with an increasing incidence over the past decades. High-level evidence has been reported for the MATRix regimen (high-dose methotrexate (HD-MTX), high-dose AraC (HD-AraC), thiotepa and rituximab) followed by high-dose chemotherapy and autologous stem cell transplantation (HCT-ASCT) supporting this approach to be considered a standard therapy in newly diagnosed PCNSL patients ≤ 70 years. However, early treatment-related toxicities (predominantly infectious complications), occurring in up to 28% per MATRix cycle, diminish its therapeutic success. Furthermore, sensitivity to first-line treatment is an independent prognostic factor for improved overall survival (OS) in PCNSL. Thus, patients achieving early partial remission (PR) after 2 cycles of MATRix might be over-treated with 4 cycles, in the context of consolidation HCT-ASCT.
METHODS
This is an open-label, multicentre, randomized phase III trial with two parallel arms. 326 immunocompetent patients with newly diagnosed PCNSL will be recruited from 37 German, 1 Austrian and 12 UK sites. Additional IELSG (International Extranodal Lymphoma Study Group) sites are planned. The objective is to demonstrate superiority of a de-escalated and optimised remission induction treatment strategy, followed by HCT-ASCT. Randomization (1:1) will be performed after completion of all screening procedures. Patients in Arm A (control treatment) will receive 4 cycles of MATRix. Patients in Arm B (experimental treatment) will receive a pre-phase (R/HD-MTX), followed by 2 cycles of MATRix. Patients in both arms achieving PR or better will proceed to HCT-ASCT (BCNU, thiotepa). The primary endpoint of the study is event-free-survival (EFS), defined as time from randomization to premature end of treatment due to any reason, lymphoma progression or death whichever occurs first. Secondary endpoints include OS, progression free survival (PFS), toxicity, neurocognitive impairment and quality of life. Minimal follow-up is 24 months.
DISCUSSION
Current treatment options for PCNSL in patients ≤ 70 years have improved remarkably over recent years. However, the potential efficacy benefits are offset by an increased incidence of short-term toxicities which can impact on treatment delivery and hence on survival outcomes. In patients ≤ 70 years with newly diagnosed PCNSL addressing the need to reduce treatment-related toxicity by de-escalating and optimising the induction phase of treatment, is a potentially attractive treatment strategy.
TRIAL REGISTRATION
German clinical trials registry DRKS00022768 registered June 10, 2021.
Topics: Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Combined Modality Therapy; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, Large B-Cell, Diffuse; Methotrexate; Quality of Life; Remission Induction; Thiotepa; Transplantation, Autologous
PubMed: 36088292
DOI: 10.1186/s12885-022-09723-w -
Polymers Aug 2022-Sulfonyl-activated aziridines are known to undergo anionic-ring-opening polymerizations (AROP) to form polysulfonyllaziridines. However, the post-polymerization...
-Sulfonyl-activated aziridines are known to undergo anionic-ring-opening polymerizations (AROP) to form polysulfonyllaziridines. However, the post-polymerization deprotection of the sulfonyl groups from polysulfonyllaziridines remains challenging. In this report, the polymerization of -butyl aziridine-1-carboxylate () is reported. has an electron-withdrawing tert-butyloxycarbonyl (BOC) group on the aziridine nitrogen. The BOC group activates the aziridine for AROP and allows the synthesis of low-molecular-weight poly() chains. A C NMR spectroscopic analysis of poly() suggested that the polymer is linear. The attainable molecular weight of poly() is limited by the poor solubility of poly() in AROP-compatible solvents. The deprotection of poly() using trifluoroacetic acid (TFA) cleanly produces linear polyethyleneimine. Overall, these results suggest that carbonyl groups, such as BOC, can play a larger role in the in the activation of aziridines in anionic polymerization and in the synthesis of polyimines.
PubMed: 36015510
DOI: 10.3390/polym14163253 -
Marine Drugs Aug 2022The development of harmless substances to replace biocide-based coatings used to prevent or manage marine biofouling and its unwanted consequences is urgent. The...
The development of harmless substances to replace biocide-based coatings used to prevent or manage marine biofouling and its unwanted consequences is urgent. The formation of biofilms on submerged marine surfaces is one of the first steps in the marine biofouling process, which facilitates the further settlement of macrofoulers. Anti-biofilm properties of a synthetic polyphenolic compound, with previously described anti-settlement activity against macrofoulers, were explored in this work. In solution this new compound was able to prevent biofilm formation and reduce a pre-formed biofilm produced by the marine bacterium, . Then, this compound was applied to a marine coating and the formation of biofilms was assessed under hydrodynamic conditions to mimic the marine environment. For this purpose, polyurethane (PU)-based coating formulations containing 1 and 2 wt.% of the compound were prepared based on a prior developed methodology. The most effective formulation in reducing the biofilm cell number, biovolume, and thickness was the PU-based coating containing an aziridine-based crosslinker and 2 wt.% of the compound. To assess the marine ecotoxicity impact of this compound, its potential to disrupt endocrine processes was evaluated through the modulation of two nuclear receptors (NRs), peroxisome proliferator-activated receptor γ (PPARγ), and pregnane X receptor (PXR). Transcriptional activation of the selected NRs upon exposure to the polyphenolic compound (10 µM) was not observed, thus highlighting the eco-friendliness towards the addressed NRs of this new dual-acting anti-macro- and anti-microfouling agent towards the addressed NRs.
Topics: Biofilms; Biofouling; Disinfectants
PubMed: 36005510
DOI: 10.3390/md20080507 -
Chemical Communications (Cambridge,... Sep 2022Electrophilic aminating reagents have seen a renaissance in recent years as effective nitrogen sources for the synthesis of unprotected amino functionalities. Based on... (Review)
Review
Electrophilic aminating reagents have seen a renaissance in recent years as effective nitrogen sources for the synthesis of unprotected amino functionalities. Based on their reactivity, several noble and non-noble transition metal catalysed amination reactions have been developed. These include the aziridination and difunctionalisation of alkenes, the amination of arenes as well as the synthesis of aminated sulfur compounds. In particular, the use of hydroxylamine-derived (N-O) reagents, such as PONT (PivONHOTf), has enabled the introduction of unprotected amino groups on various different feedstock compounds, such as alkenes, arenes and thiols. This strategy obviates undesired protecting-group manipulations and thus improves step efficiency and atom economy. Overall, this feature article gives a recent update on several reactions that have been unlocked by employing versatile hydroxylamine-derived aminating reagents, which facilitate the generation of unprotected primary, secondary and tertiary amino groups.
Topics: Alkenes; Amines; Hydroxylamine; Hydroxylamines; Indicators and Reagents; Molecular Structure
PubMed: 35993918
DOI: 10.1039/d2cc02431d -
Bone Marrow Transplantation Nov 2022Therapeutic options for patients with AML relapsing after allogeneic HCT range from chemotherapy or hypomethylating agents with or without donor lymphocyte infusions to...
Therapeutic options for patients with AML relapsing after allogeneic HCT range from chemotherapy or hypomethylating agents with or without donor lymphocyte infusions to a 2nd allogeneic HCT. Available data are based on retrospective single center or registry studies. The aim of this multicenter trial was to investigate prospectively intensive conditioning with Thiotepa, Fludarabine and Treosulfan (TFT) for 2nd allogeneic HCT from an alternative unrelated donor in patients with AML relapse > 6 months after a 1st allogeneic HCT. Primary endpoint was disease-free survival (DFS) at one year after 2nd HCT. 50 patients median age 53.5 years, in CR/PR (34%) or active relapse (66%) were included. 33 of 38 patients (86.8%) with available data achieved CR 100 days post transplant. 23 patients were alive and free of relapse at primary endpoint one year after 2nd HCT (DFS rate 0.46, 95%-CI (0.32-0.61). Three-year rates of DFS, relapse, non-relapse mortality, and overall survival were 0.24, 95%-CI (0.13-0.36); 0.36 (0.25-0.52); 0.40 (0.29-0.57); and 0.24 (0.13-0.37). Second HCT with TFT conditioning is feasible and has high anti-leukemic efficacy in chemosensitive or refractory AML relapse after prior allogeneic HCT. Still, relapse rates and NRM after 2nd allogeneic HCT remain a challenge. The trial is registered in the German Clinical Trials Registry (number DRKS00005126).
Topics: Humans; Middle Aged; Thiotepa; Transplantation Conditioning; Unrelated Donors; Retrospective Studies; Prospective Studies; Neoplasm Recurrence, Local; Vidarabine; Hematopoietic Stem Cell Transplantation; Leukemia, Myeloid, Acute
PubMed: 35982219
DOI: 10.1038/s41409-022-01777-5 -
RSC Advances Jul 2022Novel ionic liquids based on DBU and DBN halide salts were developed as a catalytic system for ring-opening of non-activated aziridines with [C]CO. The ability of ionic...
Novel ionic liquids based on DBU and DBN halide salts were developed as a catalytic system for ring-opening of non-activated aziridines with [C]CO. The ability of ionic liquids to activate aziridines represents a simple methodology for the synthesis of C-carbamates and can be extended for CO-fixation in organic and radiochemistry.
PubMed: 35975081
DOI: 10.1039/d2ra03966d