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Clinical Pharmacology and Therapeutics Jan 2024A toxicity-reduced conditioning regimen with treosulfan, fludarabine, and thiotepa in patients with high-risk β-thalassemia major has significantly improved...
A toxicity-reduced conditioning regimen with treosulfan, fludarabine, and thiotepa in patients with high-risk β-thalassemia major has significantly improved hematopoietic stem cell transplantation (HCT) outcomes. However, complications resulting from regimen-related toxicities (RRTs), mixed chimerism, and graft rejection remain a challenge. We evaluated the dose-exposure-response relationship of treosulfan and its active metabolite S, S-EBDM, in a uniform cohort of patients with β-thalassemia major to identify whether therapeutic drug monitoring (TDM) and dose adjustment of treosulfan is feasible. Plasma treosulfan/S, S-EBDM levels were measured in 77 patients using a validated liquid chromatography with tandem mass spectrometry method, and the pharmacokinetic parameters were estimated using nlmixr2. The influence of treosulfan and S, S-EBDM exposure, and GSTA1/NQO1 polymorphisms on graft rejection, RRTs, chimerism status, and 1-year overall survival (OS), and thalassemia-free survival (TFS) were assessed. We observed that treosulfan exposure was lower in patients with graft rejection than those without (1,655 vs. 2,037 mg•h/L, P = 0.07). Pharmacodynamic modeling analysis to identify therapeutic cutoff revealed that treosulfan exposure ≥1,660 mg•hour/L was significantly associated with better 1-year TFS (97% vs. 81%, P = 0.02) and a trend to better 1-year OS (90% vs. 69%, P = 0.07). Further, multivariate analysis adjusting for known pre-HCT risk factors also revealed treosulfan exposure <1,660 mg•h/L (hazard ratio (HR) = 3.23; 95% confidence interval (CI) = 1.12-9.34; P = 0.03) and GSTA1*B variant genotype (HR = 3.75; 95% CI = 1.04-13.47; P = 0.04) to be independent predictors for inferior 1-year TFS. We conclude that lower treosulfan exposure increases the risk of graft rejection and early transplant-related mortality affecting TFS. As no RRTs were observed with increasing treosulfan exposure, TDM-based dose adjustment could be feasible and beneficial.
Topics: Humans; beta-Thalassemia; Busulfan; Hematopoietic Stem Cell Transplantation; Thiotepa; Transplantation Conditioning; Graft vs Host Disease
PubMed: 37846495
DOI: 10.1002/cpt.3078 -
Blood Jun 2024In the setting of a learning collaborative, we conducted an international multicenter phase 2 clinical trial testing the hypothesis that nonmyeloablative-related...
In the setting of a learning collaborative, we conducted an international multicenter phase 2 clinical trial testing the hypothesis that nonmyeloablative-related haploidentical bone marrow transplant (BMT) with thiotepa and posttransplant cyclophosphamide (PTCy) will result in 2-year event-free survival (no graft failure or death) of at least 80%. A total of 70 participants were evaluable based on the conditioning protocol. Graft failure occurred in 8 of 70 (11.4%) and only in participants aged <18 years; all had autologous reconstitution. After a median follow-up of 2.4 years, the 2-year Kaplan-Meier-based probability of event-free survival was 82.6%. The 2-year overall survival was 94.1%, with no difference between children and adult participants. After excluding participants with graft failure (n = 8), participants with engraftment had median whole blood donor chimerism values at days +180 and +365 after transplant of 100% (n = 58), respectively, and 96.6% (57/59) were off immunosuppression 1 year after transplant. The 1-year grade 3 to 4 acute graft-versus-host disease (GVHD) rate was 10%, and the 2-year moderate-severe chronic GVHD rate was 10%. Five participants (7.1%) died from infectious complications. We demonstrate that nonmyeloablative haploidentical BMT with thiotepa and PTCy is a readily available curative therapy for most adults, even those with organ damage, compared to the more expensive myeloablative gene therapy and gene editing. Additional strategies are required for children to decrease graft failure rates. The trial was registered at www.clinicaltrials.gov as #NCT01850108.
Topics: Humans; Bone Marrow Transplantation; Male; Female; Child; Adolescent; Adult; Anemia, Sickle Cell; Graft vs Host Disease; Transplantation, Haploidentical; Child, Preschool; Young Adult; Cyclophosphamide; Transplantation Conditioning; Middle Aged; Thiotepa
PubMed: 38493482
DOI: 10.1182/blood.2023023301 -
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 -
Chem Apr 2021Organic azides have been increasingly employed as nitrogen sources for catalytic olefine aziridination due to their ease of preparation and generation of benign N as the...
Organic azides have been increasingly employed as nitrogen sources for catalytic olefine aziridination due to their ease of preparation and generation of benign N as the only byproduct. Among common organic azides, carbonyl azides have not been previously demonstrated as effective nitrogen sources for intermolecular olefin aziridination despite the synthetic utilities of N-carbonyl aziridines. As a new application of metalloradical catalysis, we have developed a catalytic system that can effectively employ the carbonyl azide TrocN for highly asymmetric aziridination of alkenes at room temperature. The resulting enantioenriched -Trocaziridines have been shown as valuable chiral synthons for stereoselective synthesis of other chiral aziridines and various chiral amines. The Co(II)-based metalloradical system, which proceeds with distinctive stepwise radical mechanism, may provide a general method for asymmetric synthesis of chiral aziridines from alkenes with organic azides.
PubMed: 33869888
DOI: 10.1016/j.chempr.2021.03.001 -
The Journal of Antibiotics Feb 2018A total synthesis of (+)-lysergic acid, which features the C-C bond formation between C10 and C11 via cleavage of an aziridine ring, was accomplished.
A total synthesis of (+)-lysergic acid, which features the C-C bond formation between C10 and C11 via cleavage of an aziridine ring, was accomplished.
Topics: Aziridines; Ergot Alkaloids; Indicators and Reagents; Lysergic Acid; Molecular Structure; Stereoisomerism
PubMed: 29375135
DOI: 10.1038/ja.2017.80 -
Organic Letters Jan 2021We report the first organocatalytic kinetic resolution of unactivated aziridines by sulfur nucleophiles with excellent enantioselectivity. A suitable chiral phosphoric...
We report the first organocatalytic kinetic resolution of unactivated aziridines by sulfur nucleophiles with excellent enantioselectivity. A suitable chiral phosphoric acid was found to catalyze the intermolecular ring opening under mild conditions, furnishing a range of highly enantioenriched β-amino thioethers and aziridines, both of which are useful synthetic building blocks.
Topics: Aziridines; Catalysis; Kinetics; Molecular Structure; Phosphoric Acids; Sulfhydryl Compounds
PubMed: 33382271
DOI: 10.1021/acs.orglett.0c04074 -
International Journal of Biological... Dec 2022In this paper, a novel grafted zeolite/FeO/chitosan (ZMC-MAH-TEPA) adsorbent was greenly synthesized and evaluated for the removal of Cr(VI) and Ag(I) in single and...
In this paper, a novel grafted zeolite/FeO/chitosan (ZMC-MAH-TEPA) adsorbent was greenly synthesized and evaluated for the removal of Cr(VI) and Ag(I) in single and bi-component solutions. The characterization data of XRF, XRD, FT-IR, VSM, TGA, BET and SEM showed the successful fabrication of the adsorbent with abundant -NH and -NH- as well as great recovery properties (11.70 emu/g). The effects of experimental parameters, including pH value, initial concentration, temperature, time, and coexisting ions on single and bi-component adsorption, were investigated. The results demonstrated that the adsorption capacities increased with the enhanced shaking time and concentration until equilibrium was reached. The optimum pH value was 3 for Cr(VI) adsorption and 5 for Ag(I) adsorption. The maximum adsorption capacities for Cr(VI) and Ag(I) ions, obtained by the Langmuir model, were 50.75 and 70.12 mg·g in single metal solutions and 45.45 and 58.94 mg·g in bi-component metal solutions (Cr(VI)/Ag(I) = 1:1), respectively. Additionally, the adsorption mechanism of Cr(VI) and Ag(I) was explained in terms of electrostatic interaction and hydrogen bonding between metal ions and -NH and -NH- in ZMC-MAH-TEPA. Taken together, this study provides a clean approach to synthesizing chitosan-based adsorbents for the efficient removal of Cr(VI) and Ag(I) ions.
Topics: Adsorption; Chitosan; Zeolites; Spectroscopy, Fourier Transform Infrared; Water Pollutants, Chemical; Kinetics; Hydrogen-Ion Concentration; Water Purification; Chromium; Ions; Magnetic Phenomena; Triethylenephosphoramide
PubMed: 36228821
DOI: 10.1016/j.ijbiomac.2022.10.044 -
Journal of the American Chemical Society Sep 2022Natural products containing an aziridine ring, such as mitomycin C and azinomycin B, exhibit antitumor activities by alkylating DNA via their aziridine rings; however,...
Natural products containing an aziridine ring, such as mitomycin C and azinomycin B, exhibit antitumor activities by alkylating DNA via their aziridine rings; however, the biosynthetic mechanisms underlying the formation of these rings have not yet been elucidated. We herein investigated the biosynthesis of vazabitide A, the structure of which is similar to that of azinomycin B, and demonstrated that Vzb10/11, with no similarities to known enzymes, catalyzed the formation of the aziridine ring via sulfate elimination. To elucidate the detailed reaction mechanism, crystallization of Vzb10/11 and the homologous enzyme, AziU3/U2, in the biosynthesis of azinomycin B was attempted, and the structure of AziU3/U2, which had a new protein fold overall, was successfully determined. The structural analysis revealed that these enzymes adjusted the dihedral angle between the amino group and the adjacent sulfate group of the substrate to almost 180° and enhanced the nucleophilicity of the C6-amino group temporarily, facilitating the S2-like reaction to form the aziridine ring. The present study reports for the first time the molecular basis for aziridine ring formation.
Topics: Aziridines; DNA; Mitomycin; Sulfates
PubMed: 35998388
DOI: 10.1021/jacs.2c07243 -
International Immunology Aug 2017Autoimmune and inflammatory conditions are frequent complications in patients with reduced numbers of T cells. Here, we describe a mouse model of thymic stromal...
Autoimmune and inflammatory conditions are frequent complications in patients with reduced numbers of T cells. Here, we describe a mouse model of thymic stromal dysplasia resulting in peripheral T-cell lymphopenia. In Foxn1:CFP-NTR transgenic mice, the bacterial nitroreductase enzyme is expressed in thymic epithelial cells and converts the prodrug CB1954 into a cytotoxic agent. This strategy enables titratable and durable destruction of thymopoietic tissue in early embryogenesis. Our results indicate that the resulting low levels of thymic capacity for T-cell production create a predisposition for the development of a complex autoimmune syndrome, chiefly characterized by inflammatory bowel disease and lymphocytic organ infiltrations. We conclude that the Foxn1:CFP-NTR transgenic mouse strain represents a suitable animal model to optimize established clinical protocols, such as thymus transplantation, to correct various forms of thymic dysplasia and to explore novel treatment options.
Topics: Anaplasia; Animals; Antineoplastic Agents; Apoptosis; Autoimmunity; Aziridines; Disease Models, Animal; Forkhead Transcription Factors; Humans; Inflammatory Bowel Diseases; Lymphopenia; Mice; Mice, Inbred C57BL; Mice, Transgenic; T-Lymphocytes; Thymus Gland
PubMed: 28992076
DOI: 10.1093/intimm/dxx048 -
Science (New York, N.Y.) Feb 2017Cysteine can be specifically functionalized by a myriad of acid-base conjugation strategies for applications ranging from probing protein function to antibody-drug...
Cysteine can be specifically functionalized by a myriad of acid-base conjugation strategies for applications ranging from probing protein function to antibody-drug conjugates and proteomics. In contrast, selective ligation to the other sulfur-containing amino acid, methionine, has been precluded by its intrinsically weaker nucleophilicity. Here, we report a strategy for chemoselective methionine bioconjugation through redox reactivity, using oxaziridine-based reagents to achieve highly selective, rapid, and robust methionine labeling under a range of biocompatible reaction conditions. We highlight the broad utility of this conjugation method to enable precise addition of payloads to proteins, synthesis of antibody-drug conjugates, and identification of hyperreactive methionine residues in whole proteomes.
Topics: Actins; Aziridines; Cysteine; Gene Editing; Gene Knockout Techniques; Immunoconjugates; Methionine; Mutation; Oxidation-Reduction; Phosphopyruvate Hydratase; Protein Domains; Proteins; Proteomics; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Sodium Hypochlorite
PubMed: 28183972
DOI: 10.1126/science.aal3316