-
Molecules (Basel, Switzerland) Oct 2022Multi-substituted pyrroles are synthesized from regiospecific aziridine ring-opening and subsequent intramolecular cyclization with a carbonyl group at the -position in...
Multi-substituted pyrroles are synthesized from regiospecific aziridine ring-opening and subsequent intramolecular cyclization with a carbonyl group at the -position in the presence of Lewis acid or protic acid. This method is highly atom economical where all the atoms of the reactants are incorporated into the final product with the removal of water. This new protocol is applied to the synthesis of various pyrroles, including natural products.
Topics: Pyrroles; Lewis Acids; Aziridines; Biological Products; Water
PubMed: 36296466
DOI: 10.3390/molecules27206869 -
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 -
Accounts of Chemical Research Aug 2020Aziridines, i.e., the smallest saturated N-heterocycles, serve as useful building blocks in synthetic organic chemistry. Because of the release of the large ring strain...
Aziridines, i.e., the smallest saturated N-heterocycles, serve as useful building blocks in synthetic organic chemistry. Because of the release of the large ring strain energy accommodated in the small ring, (ca. 27 kcal/mol), aziridines undergo ring-opening reactions with a variety of nucleophiles. Therefore, among the synthetic reactions utilizing aziridines, regioselective ring-opening substitutions of aziridines with nucleophiles, such as heteroatomic nucleophiles (e.g., amines, alcohols, and thiols) and carbonaceous nucleophiles (e.g., carbanions, organometallic reagents, and electron-rich arenes), constitute a useful synthetic methodology to synthesize biologically relevant β-functionalized alkylamines. However, the regioselection in such traditional ring-opening substitutions of aziridines is highly dependent on the substrate combination, and stereochemical control is challenging to achieve, especially in the case of Lewis acid-promoted variants. Therefore, the development of robust catalytic ring-opening functionalization methods that enable precise prediction of regioselectivity and stereochemistry is desirable. In this direction, our group focused on the highly regioselective and stereospecific nature of the stoichiometric oxidative addition elementary step of 2-substituted aziridines into Pd(0) complexes in an S2 fashion. In conjunction with the recent advancements in transition-metal-catalyzed cross-coupling reactions of alkyl pseudohalides containing a C(sp)-Q (Q = O, N, S, etc.) bond, aziridines can be used as nonclassical alkyl pseudohalides in regioselective and stereospecific cross-couplings.In this Account, starting from the background of transition-metal-catalyzed ring-opening functionalization of aziridines, our contributions to the palladium-catalyzed regioselective and stereoinvertive cross-couplings of aziridines with organoboron reagents to form C(sp)-C, C(sp)-B, and C(sp)-Si bonds have been compiled. The developed methods allow the syntheses of medicinally important amine compounds, e.g., enantioenriched β-phenethylamines, β-amino acids, and their boron and silyl surrogates, from readily available enantiopure aziridine substrates. Notably, the regioselectivity of the ring opening can be switched by appropriate selection of the catalyst (i.e., Pd/NHC vs Pd/PR systems). Computational studies rationalized the detailed mechanisms of the full catalytic cycle and the regioselectivity and stereospecificity of the reactions. The computational results suggested that the interactions operating between the Pd catalyst and aziridine substrate play important roles in determining the regioselection of the aziridine ring-opening event (i.e., oxidative addition). Also, the computational results rationalized the role of water molecules in promoting the transmetalation step through the formation of a Pd-hydroxide active intermediate. This Account evidences the benefits of synergistic collaborations between experimental and computational methods in developing novel transition-metal-catalyzed cross-coupling reactions.
PubMed: 32786337
DOI: 10.1021/acs.accounts.0c00395 -
Journal of the American Chemical Society Mar 2023Aziridines are compounds with a nitrogen-containing three-membered ring. When it is incorporated into natural products, the reactivity of the strained ring often drives...
Aziridines are compounds with a nitrogen-containing three-membered ring. When it is incorporated into natural products, the reactivity of the strained ring often drives the biological activities of aziridines. Despite its importance, the enzymes and biosynthetic strategies deployed to install this reactive moiety remain understudied. Herein, we report the use of methods to identify enzymes with potential aziridine-installing (aziridinase) functionality. To validate candidates, we reconstitute enzymatic activity and demonstrate that an iron(IV)-oxo species initiates aziridine ring closure by the C-H bond cleavage. Furthermore, we divert the reaction pathway from aziridination to hydroxylation using mechanistic probes. This observation, isotope tracing experiments using HO and O, and quantitative product analysis, provide evidence for the polar capture of a carbocation species by the amine in the pathway to aziridine installation.
Topics: Iron; Aziridines; Hydroxylation; Catalysis
PubMed: 36913534
DOI: 10.1021/jacs.2c12664 -
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 -
Organic Letters May 2019The first total synthesis of pactalactam was accomplished using substrate-controlled stereoselective aziridination and regioselective aziridine ring-opening to construct...
The first total synthesis of pactalactam was accomplished using substrate-controlled stereoselective aziridination and regioselective aziridine ring-opening to construct three continuous amino groups on an octasubstituted cyclopentane core. The cyclopentane framework was obtained by ring-closing metathesis and aldol coupling using a l-threonine-derived oxazoline compound. Cyclic urea formation, m-acetylphenyl group introduction by Chan-Lam coupling, and primary alcohol-selective acylation yielded the reported pactalactam structure. The presence of pactalactam in the fermentation broth of pactamycin-producing bacteria was also confirmed.
Topics: Acylation; Alcohols; Aziridines; Cyclopentanes; Imidazolidines; Molecular Structure; Pactamycin
PubMed: 31058517
DOI: 10.1021/acs.orglett.9b00905 -
The Journal of Organic Chemistry Jul 2022Brønsted acid- and/or Lewis acid-catalyzed selective C3-allylation and formal [3 + 2]-annulation of spiro-aziridine oxindoles with allylsilanes have been demonstrated...
Brønsted acid- and/or Lewis acid-catalyzed selective C3-allylation and formal [3 + 2]-annulation of spiro-aziridine oxindoles with allylsilanes have been demonstrated to deliver direct access to 3-allyl-3-aminomethyl oxindoles and 5-silyl methyl spiro[pyrrolidine-3,3'-oxindoles], respectively. The acid-catalyzed methods do not provide any stereoselectivity when chiral spiroaziridines are used. However, the reaction of nonracemic sprioaziridines with allyl-Grignard reagent under catalyst-free conditions afforded 3-allyl-3-aminomethyl oxindoles with good stereoselectivity (ee up to 80%). The allylation protocol is utilized for the short synthesis of coerulescine and various 5'-substituted spiro[pyrrolidine-3,3'-oxindoles].
Topics: Aniline Compounds; Aziridines; Indoles; Molecular Structure; Oxindoles; Pyrrolidines; Spiro Compounds
PubMed: 35731944
DOI: 10.1021/acs.joc.2c00863 -
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 -
Angewandte Chemie (International Ed. in... Dec 2020The success of intracellular protein therapy demands efficient delivery and selective protein activity in diseased cells. Therefore, a cascaded nanozymogen consisting of...
The success of intracellular protein therapy demands efficient delivery and selective protein activity in diseased cells. Therefore, a cascaded nanozymogen consisting of a hypoxia-activatable pro-protein, a hypoxia-inducing protein, and a hypoxia-strengthened intracellular protein delivery nanovehicle was developed. RPAB, an enzymatically inactive pro-protein of RNase, reversibly caged with hypoxia-cleavable azobenzene, was delivered with glucose oxidase (GOx) using hypoxia-responsive nanocomplexes (NCs) consisting of azobenzene-cross-linked oligoethylenimine (AOEI) and hyaluronic acid (HA). Upon NC-mediated delivery into cancer cells, GOx catalyzed glucose decomposition and aggravated tumoral hypoxia, which drove the recovery of RPAB back to the hydrolytically active RNase and expedited the degradation of AOEI to release more protein cargoes. Thus, the catalytic reaction of the nanozymogen was self-accelerated and self-cycled, ultimately leading to a cooperative anti-cancer effect between GOx-mediated starvation therapy and RNase-mediated pro-apoptotic therapy.
Topics: Aziridines; Azo Compounds; Biocatalysis; Glucose Oxidase; Humans; Hyaluronic Acid; Intracellular Signaling Peptides and Proteins; Molecular Structure; Nanoparticles; Ribonucleases; Ribonucleoproteins, Small Nuclear
PubMed: 32562432
DOI: 10.1002/anie.202004008