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BioRxiv : the Preprint Server For... Aug 2023Nitriles are uncommon in nature and are typically constructed from oximes via the oxidative decarboxylation of amino acid substrates or from the derivatization of...
Nitriles are uncommon in nature and are typically constructed from oximes via the oxidative decarboxylation of amino acid substrates or from the derivatization of carboxylic acids. Here we report a third strategy of nitrile biosynthesis featuring the cyanobacterial nitrile synthase AetD. During the biosynthesis of the 'eagle-killing' neurotoxin, aetokthonotoxin, AetD converts the alanyl side chain of 5,7-dibromo-L-tryptophan to a nitrile. Employing a combination of structural, biochemical, and biophysical techniques, we characterized AetD as a non-heme diiron enzyme that belongs to the emerging Heme Oxygenase-like Diiron Oxidase and Oxygenase (HDO) superfamily. High-resolution crystal structures of AetD together with the identification of catalytically relevant products provide mechanistic insights into how AetD affords this unique transformation that we propose proceeds via an aziridine intermediate. Our work presents a new paradigm for nitrile biogenesis and portrays a substrate binding and metallocofactor assembly mechanism that may be shared among other HDO enzymes.
PubMed: 37577561
DOI: 10.1101/2023.08.03.551874 -
Transplantation and Cellular Therapy Aug 2023Second allogeneic hematopoietic stem cell transplantation (HSCT) is a treatment option for patients with acute leukemia who relapse after a first HSCT. Although...
Second allogeneic hematopoietic stem cell transplantation (HSCT) is a treatment option for patients with acute leukemia who relapse after a first HSCT. Although myeloablative conditioning (MAC) regimens before the first HSCT are considered superior to reduced- intensity conditioning (RIC) in terms of disease control in acute leukemia patients, the optimal conditioning regimen for the second allogeneic HSCT remains controversial. The most important prognostic factors are the remission disease phase at the time of the second HSCT and an interval >12 months from the first HSCT to the second HSCT. Total marrow irradiation (TMI) is an advanced high-precision radiation treatment that delivers therapeutic doses over extensively selected targets while substantially reducing radiation to vital organs compared to conventional total body irradiation (TBI). Here we report the results of a retrospective analysis of second allogeneic HSCT treated with TMI as an MAC regimen with the intent of limiting toxicity. We investigated the efficacy of high dose per fraction TMI in combination with thiotepa, fludarabine, and melphalan in 13 consecutive patients with acute leukemia who had relapsed after a first allogeneic HSCT treated between March 2018 and November 2021. Donor type was haploidentical in 10 patients, unrelated in 2 patients, and HLA-identical sibling in 1 patient. The conditioning regimen consisted of 8 Gy TMI in 5 patients on days -8 and -7 and 12 Gy TMI in 8 patients on days -9 to -7, plus thiotepa 5 mg/kg on day -6, fludarabine 50 mg/day on days -5 to -3, and melphalan 140 mg/day on day -2. The TMI was delivered at the dosage og 4 GY for 2 consecutive days (total = 8 GY) or for 3 consecutive days (total = 12 GY). The median patient age was 45 years (range, 19 to 70 years); 7 patients were in remission, and 6 had active disease at the time of their second allogeneic HSCT. The median time to a neutrophil count of >.5 × 10/L was 16 days (range, 13 to 22 days), and the median time to a platelet count of >20 × 10/L was 20 days (range, 14 to 34 days). All patients showed complete donor chimerism on day +30 post-transplantation. The cumulative incidence of grade I-II acute graft-versus-host disease (GVHD) was 43%, and that of chronic GVHD was 30%. The median duration of follow-up was 1121 days (range, 200 to 1540 days). Day +30 and +100 transplantation-related mortality (TRM) was 0. The overall cumulative incidence of TRM, relapse rate, and disease free-survival were 27%, 7%, and 67%, respectively. This retrospective study demonstrates the safety and efficacy of a hypofractionated TMI conditioning regimen in patients with acute leukemia undergoing second HSCT with encouraging outcomes in terms of engraftment, early toxicity, GVHD, and relapse.
Topics: Humans; Young Adult; Adult; Middle Aged; Aged; Retrospective Studies; Bone Marrow; Melphalan; Thiotepa; Leukemia, Myeloid, Acute; Hematopoietic Stem Cell Transplantation; Graft vs Host Disease; Acute Disease; Recurrence
PubMed: 37094701
DOI: 10.1016/j.jtct.2023.04.014 -
RSC Advances May 2024Cyclic -sulfonyl aldimines are well-known aza-[2]-synthons for various [2 + ] annulation reactions. Herein we describe a novel base mediated [2 + 1] annulation and a...
Base mediated aza-[2 + 1] annulation and regioselective aziridine ring-opening cascade: mild synthesis of functionalized -amino ketones from cyclic -sulfonyl aldimines and -carbonyl sulfonium salts.
Cyclic -sulfonyl aldimines are well-known aza-[2]-synthons for various [2 + ] annulation reactions. Herein we describe a novel base mediated [2 + 1] annulation and a regioselective aziridine ring-opening reaction cascade, which provides an efficient and distinct synthetic strategy from readily available cyclic -sulfonyl aldimines and -carbonyl sulfonium salts leading to -amino ketone derivatives through the corresponding fused tri-substituted aziridines. This one-pot, two-step process involves formation of C-C and C-N bonds and subsequent cleavage of a C-N bond. The features of the developed reaction include the use of mild reaction conditions, broad substrate scope, and excellent yields. The synthetic utility of this approach was demonstrated by gram-scale operation and further product derivatizations.
PubMed: 38808243
DOI: 10.1039/d4ra02817a -
Environmental Science and Pollution... Nov 2023A series of fibrous aminated adsorbents for CO adsorption were prepared by covalent incorporation of poly (glycidyl methacrylate) (PGMA) by graft copolymerization of GMA...
A series of fibrous aminated adsorbents for CO adsorption were prepared by covalent incorporation of poly (glycidyl methacrylate) (PGMA) by graft copolymerization of GMA onto electron beam (EB) irradiated polyethylenepolypropylene (PE/PP) fibrous sheets and subsequent amination with ethylenediamine (EDA), diethylenetriamine (DETA), or tetraethylenepentamine (TEPA). The physico-chemical properties of the adsorbents were evaluated using Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), thermogravimetric (TGA), X-ray diffraction (XRD), and Brunauer-Emmett-Teller (BET) analysis. All the adsorbents displayed typic primary and secondary amine features combined with a decrease in both of crystallinity and surface area of PE/PP, and such a decrease was higher in adsorbents with longer aliphatic chain of the amine. Of all adsorbents, TEPA-containing fibres showed the highest CO adsorption capacity and thus was further investigated for CO capture from CO/CH mixtures of different gas ratios under various pressures and temperatures. The selectivity of CO over CH and equilibrium isotherms, kinetics, and thermodynamics of the adsorption on the fibrous aminated adsorbent were all investigated. The Sips model was found to best fit the isotherm of CO adsorption suggesting the presence of a combination of monolayer and multilayer adsorptions. The adsorption kinetic data was found to best fit Elovich model reflecting chemisorption. The ΔG°, ΔS°, and ΔH° showed positive values suggesting that the adsorption of CO on the present fibrous adsorbent was non-spontaneous with an increase in randomness implying that the process was endothermic. Overall, it can be suggested that PE/PP-g-PGMA/TEPA adsorbent has a strong potential for separation of CO from NG.
Topics: Carbon Dioxide; Adsorption; Thermodynamics; Temperature; Spectroscopy, Fourier Transform Infrared; Triethylenephosphoramide; Kinetics; Hydrogen-Ion Concentration; Water Pollutants, Chemical
PubMed: 37121947
DOI: 10.1007/s11356-023-26913-6 -
Molecules (Basel, Switzerland) Mar 2024A series of optically pure aziridine phosphines and their corresponding phosphine oxides were synthesized through established chemical methodologies. The compounds were...
A series of optically pure aziridine phosphines and their corresponding phosphine oxides were synthesized through established chemical methodologies. The compounds were systematically investigated for their biological properties. Notably, all synthesized compounds demonstrated moderate antibacterial activity only against the reference strain of . However, compounds and exhibited noteworthy cell viability inhibition of human cervical epithelioid carcinoma HeLa cells and endometrial adenocarcinoma Ishikawa cells. Further studies of these compounds revealed additional biological effects, including disruption of the cell membrane in high concentrations, cell cycle arrest in the S phase, and the induction of reactive oxygen species (ROS). Comparative analysis of the two classes of chiral organophosphorus derivatives of aziridines indicated that chiral phosphine oxides displayed significantly higher biological activity. Consequently, these findings suggest that chiral phosphine oxides may be potential candidates for the development of anticancer drugs. In light of the significant interest in preparations whose structure is based on a three-membered aziridine ring in terms of potential anticancer therapy, this research fits into the current research trend and should constitute a valuable addition to the current state of knowledge and the existing library of aziridine derivatives with anticancer properties.
Topics: Humans; HeLa Cells; Aziridines; Oxides; Phosphines
PubMed: 38611710
DOI: 10.3390/molecules29071430 -
Angewandte Chemie (International Ed. in... Jan 2024N-Trifluoromethylated organics may be applied in drug design, agrochemical synthesis, and materials science, among other areas. Yet, despite recent advances in the...
N-Trifluoromethylated organics may be applied in drug design, agrochemical synthesis, and materials science, among other areas. Yet, despite recent advances in the synthesis of aliphatic, cyclic and heterocyclic N-trifluoromethyl compounds, no strategy based on trifluoromethyl nitrene has hitherto been explored. Here we describe the formation of triplet trifluoromethyl nitrene from azidotrifluoromethane, a stable and safe-to-use precursor, by visible light photocatalysis. The addition of CF N to alkenes via biradical intermediates afforded previously unknown aziridines substituted with trifluoromethyl group on the nitrogen atom. The obtained aziridines were converted into either N-trifluoromethylimidazolines, via formal [3+2] cycloaddition with nitriles, mediated by a Lewis acid, or into N-trifluoromethylaldimines, via ring opening and aryl group migration mediated by a strong Brønsted acid. Our findings open new opportunities for the development of novel classes of N-CF compounds with possible applications in the life sciences.
PubMed: 38081132
DOI: 10.1002/anie.202315162 -
Trends in Chemistry Feb 2024
PubMed: 38827493
DOI: 10.1016/j.trechm.2023.12.003 -
Molecules (Basel, Switzerland) Oct 2023Success of gene therapy relies on the durable expression and activity of transgene in target tissues. In vivo molecular imaging approaches using positron emission...
Success of gene therapy relies on the durable expression and activity of transgene in target tissues. In vivo molecular imaging approaches using positron emission tomography (PET) can non-invasively measure magnitude, location, and durability of transgene expression via direct transgene or indirect reporter gene imaging in target tissues, providing the most proximal PK/PD biomarker for gene therapy trials. Herein, we report the radiosynthesis of a novel PET tracer [F]AGAL, targeting alpha galactosidase A (α-GAL), a lysosomal enzyme deficient in Fabry disease, and evaluation of its selectivity, specificity, and pharmacokinetic properties in vitro. [F]AGAL was synthesized via a Cu-catalyzed click reaction between fluorinated pentyne and an aziridine-based galactopyranose precursor with a high yield of 110 mCi, high radiochemical purity of >97% and molar activity of 6 Ci/µmol. The fluorinated AGAL probe showed high α-GAL affinity with of 30 nM, high pharmacological selectivity (≥50% inhibition on >160 proteins), and suitable pharmacokinetic properties (moderate to low clearance and stability in plasma across species). In vivo [F]AGAL PET imaging in mice showed high uptake in peripheral organs with rapid renal clearance. These promising results encourage further development of this PET tracer for in vivo imaging of α-GAL expression in target tissues affected by Fabry disease.
Topics: Mice; Animals; alpha-Galactosidase; Fabry Disease; Positron-Emission Tomography; Radiopharmaceuticals; Hydrolases; Fluorine Radioisotopes
PubMed: 37894622
DOI: 10.3390/molecules28207144 -
The Journal of Organic Chemistry Mar 2024Aziridines are important structural motifs and intermediates, and several synthetic strategies for the direct aziridination of alkenes have been introduced. However,...
Aziridines are important structural motifs and intermediates, and several synthetic strategies for the direct aziridination of alkenes have been introduced. However, many of these strategies require an excess of activated alkene, suffer from competing side-reactions, have limited functional group tolerance, or involve precious transition metal-based catalysts. Herein, we demonstrate the direct aziridination of alkenes by combining sulfonyl azides as a triplet nitrene source with a catalytic amount of an organic dye functioning as photosensitizer. We show how the nature of the sulfonyl azide, in combination with the triplet-excited state energy of the photosensitizer, affects the aziridination yield and provide a mechanistic rationale to account for the observed dependence of the reaction yield on the nature of the organic dye and sulfonyl azide reagents. The optimized reaction conditions enable the aziridination of structurally diverse and complex alkenes, carrying various functional groups, with the alkene as the limiting reagent.
PubMed: 38358354
DOI: 10.1021/acs.joc.3c02709 -
Organic Letters Dec 2023A Cu-catalyzed coupling of cyclic imino esters with 2-azirines has been developed to synthesize novel optically active aziridines in high yields with excellent levels of...
A Cu-catalyzed coupling of cyclic imino esters with 2-azirines has been developed to synthesize novel optically active aziridines in high yields with excellent levels of diastereo- and enantioselectivities under mild conditions. This novel protocol features a broad substrate scope and good functional group compatibility, and it enriches the existing reaction type of rapid synthesis of optically active aziridines bearing vicinal tetrasubstituted stereogenic carbon centers.
PubMed: 37975634
DOI: 10.1021/acs.orglett.3c03565