-
Journal of the American Chemical Society Mar 2023An electrochemically driven nickel-catalyzed enantioselective reductive cross-coupling of aryl aziridines with alkenyl bromides has been developed, affording...
An electrochemically driven nickel-catalyzed enantioselective reductive cross-coupling of aryl aziridines with alkenyl bromides has been developed, affording enantioenriched β-aryl homoallylic amines with excellent -selectivity. This electroreductive strategy proceeds in the absence of heterogeneous metal reductants and sacrificial anodes by employing constant current electrolysis in an undivided cell with triethylamine as a terminal reductant. The reaction features mild conditions, remarkable stereocontrol, broad substrate scope, and excellent functional group compatibility, which was illustrated by the late-stage functionalization of bioactive molecules. Mechanistic studies indicate that this transformation conforms with a stereoconvergent mechanism in which the aziridine is activated through a nucleophilic halide ring-opening process.
PubMed: 36881734
DOI: 10.1021/jacs.2c12869 -
Medical Sciences (Basel, Switzerland) Jan 2023In primary central nervous system lymphoma, two-year progression-free survival rates of up to 63 percent have been reported for first-line autologous stem cell...
Thiotepa, Busulfan, Cyclophosphamide: Effective but Toxic Conditioning Regimen Prior to Autologous Hematopoietic Stem Cell Transplantation in Central Nervous System Lymphoma.
In primary central nervous system lymphoma, two-year progression-free survival rates of up to 63 percent have been reported for first-line autologous stem cell transplantation after conditioning with the thiotepa busulfan cyclophosphamide regimen. However, 11 percent of the patients died due to toxicity. Besides conventional survival, progression-free survival and treatment related mortality analyses, a competing-risk analysis was applied to our cohort of twenty-four consecutive patients with primary or secondary central nervous system lymphoma who underwent autologous stem cell transplantation after thiotepa busulfan cyclophosphamide conditioning. The two-year overall survival and progression-free survival rates were 78 percent and 65 percent, respectively. The treatment-related mortality rate was 21 percent. The competing risks analysis demonstrate that age 60 or over and the infusion of less than 4.6 × 106/kg CD34+ stem cells were significant adverse prognostic factors for overall survival. Autologous stem cell transplantation with thiotepa busulfan cyclophosphamide conditioning was associated with sustained remission and survival. Nevertheless, the intensive thiotepa busulfan cyclophosphamide conditioning regimen was highly toxic, especially in older patients. Thus, our results suggest that future studies should aim at identifying the subgroup of patients who will really benefit of the procedure and/or to reduce the toxicity of future conditioning regimen.
Topics: Humans; Aged; Middle Aged; Thiotepa; Hematopoietic Stem Cell Transplantation; Busulfan; Transplantation, Autologous; Antineoplastic Combined Chemotherapy Protocols; Lymphoma; Cyclophosphamide; Central Nervous System
PubMed: 36810481
DOI: 10.3390/medsci11010014 -
Nature Communications Feb 2023Azepinone derivatives are privileged in organic synthesis and pharmaceuticals. Synthetic approaches to these frameworks are limited to complex substrates, strong bases,...
Azepinone derivatives are privileged in organic synthesis and pharmaceuticals. Synthetic approaches to these frameworks are limited to complex substrates, strong bases, high power UV light or noble metal catalysis. We herein report a mild synthesis of azepinone derivatives by a photochemical generation of 2-aryloxyaryl nitrene, [2 + 1] annulation, ring expansion/water addition cascade reaction without using any metal catalyst. Among the different nitrene precursors tested, 2-aryloxyaryl azides performed best under blue light irradiation and Brønsted acid catalysis. The reaction scope is broad and the obtained products underwent divergent transformations to afford other related compounds. A computational study suggests a pathway involving a step-wise aziridine formation, followed by a ring-expansion to the seven-membered heterocycle. Finally, water is added in a regio-selective manner, this is accelerated by the added TsOH.
PubMed: 36788212
DOI: 10.1038/s41467-023-36190-z -
Molecules (Basel, Switzerland) Feb 2023Simple and efficient strategies for the syntheses of enantiomerically enriched functionalized diethyl 2-amino-, 2,3-diamino- and 2-amino-3-hydroxypropylphosphonates have...
Simple and efficient strategies for the syntheses of enantiomerically enriched functionalized diethyl 2-amino-, 2,3-diamino- and 2-amino-3-hydroxypropylphosphonates have been developed starting from, respectively, -protected (aziridin-2-yl)methylphosphonates, employing a regioselective aziridine ring-opening reaction with corresponding nucleophiles. Diethyl ()- and ()-2-(-Boc-amino)propylphosphonates were obtained via direct regiospecific hydrogenolysis of the respective enantiomer of ()- and ()--Boc-(aziridin-2-yl)methylphosphonates. N-Boc-protected ()- and ()-2,3-diaminopropylphosphonates were synthesized from ()- and ()--Bn-(aziridin-2-yl)methylphosphonates via a regiospecific ring-opening reaction with neat trimethylsilyl azide and subsequent reduction of ()- and ()-2-(-Boc-amino)-3-azidopropylphosphonates using triphenylphosphine. On the other hand, treatment of the corresponding ()- and ()--Bn-(aziridin-2-yl)methylphosphonates with glacial acetic acid led regiospecifically to the formation of ()- and (S)-2-(-Bn-amino)-3-acetoxypropylphosphonates.
PubMed: 36771131
DOI: 10.3390/molecules28031466 -
Angewandte Chemie (Weinheim An Der... 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: 38516047
DOI: 10.1002/ange.202217064 -
Communications Chemistry Jul 2022Nitrene transfer chemistry is an effective strategy for introducing C-N bonds, which are ubiquitous in pharmaceuticals, agrochemicals and diverse bioactive natural...
Nitrene transfer chemistry is an effective strategy for introducing C-N bonds, which are ubiquitous in pharmaceuticals, agrochemicals and diverse bioactive natural products. The development of chemical methodology that can functionalize unique sites within natural products through nitrene transfer remains a challenge in the field. Herein, we developed copper catalyzed chemoselective allylic C-H amination and catalyst-free visible-light induced aziridination of alkenes through nitrene transfer. In general, both reactions tolerate a wide range of functional groups and occur with predictable regioselectivity. Furthermore, combination of these two methods enable the intermolecular chemo-selective late-stage amination of biologically active natural products, leading to C-H amination or C=C aziridination products in a tunable way. A series of control experiments indicate two-step radical processes were involved in both reaction systems.
PubMed: 36697627
DOI: 10.1038/s42004-022-00692-6 -
Molecules (Basel, Switzerland) Dec 2022A type of MCM-41 supported dicationic imidazolium ionic liquid nanocatalyst has been synthesized and found to be competent for the synthesis of 2-oxazolidinones through...
Novel MCM-41 Supported Dicationic Imidazolium Ionic Liquids Catalyzed Greener and Efficient Regioselective Synthesis of 2-Oxazolidinones from Aziridines and Carbon Dioxide.
A type of MCM-41 supported dicationic imidazolium ionic liquid nanocatalyst has been synthesized and found to be competent for the synthesis of 2-oxazolidinones through the sustainable chemical conversion of CO with aziridines. It was shown that the highest efficiency was achieved in the cycloaddition of a series of aziridines and CO in the presence of a catalytic amount of the solid catalyst MCM-41@ILLaCl under mild conditions. Merits of this meticulously designed protocol are the use of a novel supported ionic liquid catalyst, the easy work-up process, good to excellent yields, a short reaction time, and purification without column chromatography. Overall, the present protocol of synthesizing 2-oxazolidinones under cocatalyst- and solvent-free conditions using MCM-41@ILLaCl is promising for industrial applications.
Topics: Carbon Dioxide; Ionic Liquids; Oxazolidinones; Aziridines; Catalysis
PubMed: 36615437
DOI: 10.3390/molecules28010242 -
Transplantation and Cellular Therapy Mar 2023Allogenic hematopoietic cell transplantation (HCT) is the best curative approach for patients with severe aplastic anemia (SAA). The outcomes of HCT from haploidentical...
Impact of Conditioning Regimen and Graft-versus-Host Disease Prophylaxis on The Outcome of Haploidentical Peripheral Blood Stem Cell Transplantation for High-Risk Severe Aplastic Anemia in Children and Young Adults: A Report from the Pediatric Severe Aplastic Anemia Consortium of India.
Allogenic hematopoietic cell transplantation (HCT) is the best curative approach for patients with severe aplastic anemia (SAA). The outcomes of HCT from haploidentical family donors (HFDs) have improved, making it a feasible option for patients lacking an HLA-identical donor. However, data on HFD-HCT for younger patients with SAA is sparse. In this multicenter retrospective study, we evaluated the outcomes of 79 patients undergoing HFD-HCT for SAA. All the patients were heavily pretransfused, the median time to HCT was >12 months, and 67% had failed previous therapies. Conditioning was based on fludarabine (Flu)-cyclophosphamide (Cy)-antithymocyte globulin (ATG)/total body irradiation (TBI) with or without thiotepa/melphalan (TT/Mel). Post-transplantation Cy (PTCy) and calcineurin inhibitors (CNIs)/sirolimus were used as graft-versus-host disease (GVHD) prophylaxis with or without abatacept. The rate of primary graft failure (PGF) was 16.43% overall, lower in patients conditioned with TT/Mel. The incidences of acute and chronic GVHD were 26.4% and 18.9%, respectively. At a median follow-up of 48 months, the overall survival (OS) and event-free survival (EFS) were 61.6% and 58.1%, respectively. Both OS and EFS were better in the TT/Mel recipients and with abatacept as GVHD prophylaxis. On multivariate analysis, the use of abatacept was found to favorably impact the outcome variables, including GVHD and EFS. Our study suggests that PTCy-based HFD-HCT is a reasonable option for young patients with high-risk SAA, in whom optimization of conditioning and GVHD prophylaxis might further improve outcomes.
Topics: Humans; Child; Young Adult; Peripheral Blood Stem Cell Transplantation; Anemia, Aplastic; Abatacept; Retrospective Studies; Cyclophosphamide; Graft vs Host Disease; Thiotepa
PubMed: 36572385
DOI: 10.1016/j.jtct.2022.12.010 -
Journal of Cancer Research and Clinical... Aug 2023Primary lymphomatoid granulomatosis of the CNS (CNS-LG) is a rare lymphoid neoplasia associated Epstein-Barr Virus (EBV) and often accompanied by immunodeficiencies. No...
Primary lymphomatoid granulomatosis of the CNS (CNS-LG) is a rare lymphoid neoplasia associated Epstein-Barr Virus (EBV) and often accompanied by immunodeficiencies. No treatment standards have been defined yet. However, due to often devastating neurologic sequelae and based on similarities to diffuse large B-cell lymphoma, curative treatment requires intensive therapy protocols resembling protocols applied in CNS lymphoma. Here, the clinical courses and treatments of four primary CNS-LG patients in analogy to aggressive CNS-lymphomas including methotrexate, thiotepa, cytarabine, carmustine, and rituximab are presented. This is the first report on high-dose chemotherapy with CNS-directed drugs and autologous blood stem cell transplantation in primary CNS-LG.
Topics: Lymphomatoid Granulomatosis; Methotrexate; Thiotepa; Cytarabine; Carmustine; Rituximab; Central Nervous System Viral Diseases; Epstein-Barr Virus Infections; Humans; Antineoplastic Agents; Male; Female; Adult; Middle Aged; Peripheral Blood Stem Cell Transplantation; Transplantation, Autologous; Antineoplastic Combined Chemotherapy Protocols; Treatment Outcome
PubMed: 36566338
DOI: 10.1007/s00432-022-04531-y -
Supportive Care in Cancer : Official... Dec 2022Although over 60% of patients with hematologic cancer report distressing fatigue, they often do not receive recommendations on fatigue management strategies. The aim... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Although over 60% of patients with hematologic cancer report distressing fatigue, they often do not receive recommendations on fatigue management strategies. The aim of this pilot study was to estimate the feasibility of therapeutic education and physical activity (TEPA) by measuring the patients' adherence to this multidimensional intervention. The secondary aim was to estimate the impact of TEPA on clinical outcomes.
METHODS
Patients with hematologic cancer participated in this single-center, open-label, randomized controlled trial. The control group (CG) received two educational group sessions on fatigue and physical activity. The experimental group (EG) received the two educational sessions plus six weekly individual sessions aimed at implementing a personalized physical exercise program. Follow-ups were at 1, 3, and 7 months.
RESULTS
Forty-six patients referred to chemotherapy were included, corresponding to 54% of recruitment rate. Adherence reached 90% in the EG and 68% in the CG. Most patients (65% in EG and 64% in CG) attended a minimum of 80% of the planned sessions. Overall retention rate was 87% (85% in EG and 91% in CG). No adverse events were registered. No between-group differences were detected in fatigue (FACIT-F), psychological distress (NCCN Distress Thermometer), QoL (EORTC QLQ-C30), or functional exercise capacity (TUG test and 6MWT). Adherence to an active lifestyle, measured by a semi-structured interview, increased from 56.5 to 84% in the EG at 7 months (p = 0.02), whereas it decreased slightly in the CG (from 47.8 to 42.9%).
CONCLUSION
Multidimensional rehabilitation interventions are feasible and safe in this population, and larger trials should focus on the efficacy of such approaches on clinically relevant outcomes.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03403075.
Topics: Humans; Quality of Life; Pilot Projects; Exercise; Fatigue; Hematologic Neoplasms; Triethylenephosphoramide
PubMed: 36534365
DOI: 10.1007/s00520-022-07530-4