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Lipid Isobaric Mass Tagging for Enhanced Relative Quantification of Unsaturated -Positional Isomers.ACS Measurement Science Au Apr 2024Changes in the levels of lipid -positional isomers are associated with perturbation of the physiological environment within the biological system. Consequently, knowing...
Changes in the levels of lipid -positional isomers are associated with perturbation of the physiological environment within the biological system. Consequently, knowing the concentrations of these lipids holds significant importance for unraveling their involvement in disease diagnosis and pathological mechanisms. However, existing methods for lipid quantification often fall short in accuracy due to the structural diversity and isomeric forms of lipids. To address this challenge, we have developed an aziridine-based isobaric tag labeling strategy that allows (i) differentiation and (ii) enhanced relative quantification of lipid -positional isomers from distinct samples in a single run. The methodology enabled by aziridination, isobaric tag labeling, and lithiation has been applied to various phospholipids, enabling the determination of the -positions of fatty acyl chains and enhanced relative quantification. The analysis of lipid extracts demonstrated the enhanced determination of the concentration ratios of lipid isomers by measuring the intensity ratios of mass reporters released from -positional diagnostic ions. Moreover, we applied the method to the analysis of human colon cancer plasma. Intriguingly, 17 PC lipid -positional isomers were identified and quantified simultaneously, and among them, 7 showed significant abundance changes in the colon cancer plasma, which can be used as potential plasma markers for diagnosis of human colon cancer.
PubMed: 38645577
DOI: 10.1021/acsmeasuresciau.3c00062 -
Angewandte Chemie (International Ed. in... Jun 2024The one-pot synthesis of λ-dibenzothiophen-5-imino-N-dibenzothiophenium triflate (1) in multigram scale is reported. This compound reacts with Rh(esp)...
The one-pot synthesis of λ-dibenzothiophen-5-imino-N-dibenzothiophenium triflate (1) in multigram scale is reported. This compound reacts with Rh(esp) (esp=α,α,α',α'-tetramethyl-1,3-benzenedipropionic acid) generating a Rh-coordinated sulfonitrene species, which is able to transfer the electrophilic nitrene moiety to olefins. When indenes are used as substrates, isoquinolines are obtained in good yields. We assumed that after formation of the corresponding N-sulfonio aziridine, a ring expansion occurs via selective C-C bond cleavage and concomitant elimination of dibenzothiophene. Unexpectedly, a similar protocol transforms 1-arylcyclobutenes into 1-cyano-1-arylcyclopropanes. Our calculations indicate that aziridination is not favored in this case; instead, sulfilimine-substituted cyclobutyl carbocations are initially formed, and these evolve to the isolated cyclopropanes via ring contraction. Both procedures are operationally simple, tolerate a range of functional groups, including oxidation-sensitive alcohols and aldehydes, and enable the convenient preparation of valuable N-labelled products. These results demonstrate the potential of 1 to provide alternative pathways for the selective transfer of N-atoms in organic molecules.
PubMed: 38623698
DOI: 10.1002/anie.202403826 -
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 -
ACS Omega Apr 2024The bipodal compounds [(TMGbiphen)Cu-NCMe](PF) (R = Me, Ar (4-CFPh-)) and [(TMGbiphen)Cu-I] have been synthesized with ligands that feature a diarylmethyl- and...
The bipodal compounds [(TMGbiphen)Cu-NCMe](PF) (R = Me, Ar (4-CFPh-)) and [(TMGbiphen)Cu-I] have been synthesized with ligands that feature a diarylmethyl- and triaryl-amine framework and superbasic tetramethylguanidinyl residues (TMG). The cationic Cu(I) sites mediate catalytic nitrene-transfer reactions between the imidoiodinane PhI = NTs (Ts = tosyl) and a panel of styrenes in MeCN, to afford aziridines, demonstrating comparable reactivity profiles. The copper reagents have been further explored to execute C-H amination reactions with a variety of aliphatic and aromatic hydrocarbons and two distinct nitrene sources PhI = NTs and PhI = NTces (Tces = 2,2,2-trichloroethylsulfamate) in benzene/HFIP (10:2 v/v). Good yields have been obtained for sec-benzylic and tert-C-H bonds of various substrates, especially with the more electron-deficient catalyst [(TMGbiphen)Cu-NCMe](PF). In conjunction with earlier studies, the order of reactivity of these bipodal cationic reagents as a function of the metal employed is established as Cu > Fe > Co ≥ Mn. However, as opposed to the base-metal analogues, the bipodal Cu reagents are less reactive than a similar tripodal Cu catalyst. The observed fluorophilicity of the bipodal Cu compounds may provide a deactivation pathway.
PubMed: 38585072
DOI: 10.1021/acsomega.4c00909 -
Annals of Hematology Jun 2024Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive myeloid malignancy associated with a poor prognosis. Although allogeneic hematopoietic stem...
Thiotepa-busulfan-fludarabine-based conditioning as a promising approach prior to allogeneic hematopoietic stem cell transplantation in patients with blastic plasmacytoid dendritic cell neoplasm.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive myeloid malignancy associated with a poor prognosis. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) has emerged as a potential treatment strategy for BPDCN, standardized conditioning regimens remain lacking. In this manuscript, we present two cases of BPDCN that were treated with a thiotepa-busulfan-fludarabine (TBF)-based conditioning regimen prior to allo-HSCT. Both cases demonstrated complete remission post-transplantation, sustained donor chimerism, and remission maintenance, suggesting the potential efficacy of the TBF conditioning regimen for BPDCN transplantation. Given the small sample size in our study, we emphasize caution and advocate for larger studies to confirm the efficacy of TBF in the treatment of BPDCN.
Topics: Humans; Hematopoietic Stem Cell Transplantation; Vidarabine; Transplantation Conditioning; Dendritic Cells; Thiotepa; Male; Busulfan; Middle Aged; Hematologic Neoplasms; Female; Transplantation, Homologous; Adult; Antineoplastic Combined Chemotherapy Protocols; Allografts
PubMed: 38584216
DOI: 10.1007/s00277-024-05749-1 -
Journal of the American Chemical Society Apr 2024Herein, we report that readily accessible azoxy-triazenes can serve as nitrogen atom sources under visible light excitation for the phthalimido-protected aziridination...
Herein, we report that readily accessible azoxy-triazenes can serve as nitrogen atom sources under visible light excitation for the phthalimido-protected aziridination of alkenes. This approach eliminates the need for external oxidants, precious transition metals, and photocatalysts, marking a departure from conventional methods. The versatility of this transformation extends to the selective aziridination of both activated and unactivated multisubstituted alkenes of varying electronic profiles. Notably, this process avoids the formation of competing C-H insertion products. The described protocol is operationally simple, scalable, and adaptable to photoflow conditions. Mechanistic studies support the idea that the photofragmentation of azoxy-triazenes results in the generation of a free singlet nitrene. Furthermore, a mild photoredox-catalyzed N-N cleavage of the protecting group to furnish the free aziridines is reported. Our findings contribute to the advancement of sustainable and practical methodologies for the synthesis of nitrogen-containing compounds, showcasing the potential for broader applications in synthetic chemistry.
PubMed: 38522088
DOI: 10.1021/jacs.3c14713 -
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 -
Biopharmaceutics & Drug Disposition Apr 2024AST-001 is a chemically synthesized inactive nitrogen mustard prodrug that is selectively cleaved to a cytotoxic aziridine (AST-2660) via aldo-keto reductase family 1...
AST-001 is a chemically synthesized inactive nitrogen mustard prodrug that is selectively cleaved to a cytotoxic aziridine (AST-2660) via aldo-keto reductase family 1 member C3 (AKR1C3). The purpose of this study was to investigate the pharmacokinetics and tissue distribution of the prodrug, AST-001, and its active metabolite, AST-2660, in mice, rats, and monkeys. After single and once daily intravenous bolus doses of 1.5, 4.5, and 13.5 mg/kg AST-001 to Sprague-Dawley rats and once daily 1 h intravenous infusions of 0.5, 1.5, and 4.5 mg/kg AST-001 to cynomolgus monkeys, AST-001 exhibited dose-dependent pharmacokinetics and reached peak plasma levels at the end of the infusion. No significant accumulation and gender differences were observed after 7 days of repeated dosing. In rats, the half-life of AST-001 was dose independent and ranged from 4.89 to 5.75 h. In cynomolgus monkeys, the half-life of AST-001 was from 1.66 to 5.56 h and increased with dose. In tissue distribution studies conducted in Sprague-Dawley rats and in liver cancer PDX models in female athymic nude mice implanted with LI6643 or LI6280 HepG2-GFP tumor fragments, AST-001 was extensively distributed to selected tissues. Following a single intravenous dose, AST-001 was not excreted primarily as the prodrug, AST-001 or the metabolite AST-2660 in the urine, feces, and bile. A comprehensive analysis of the preclinical data and inter-species allometric scaling were used to estimate the pharmacokinetic parameters of AST-001 in humans and led to the recommendation of a starting dose of 5 mg/m in the first-in-human dose escalation study.
Topics: Animals; Female; Mice; Rats; Aldo-Keto Reductase Family 1 Member C3; Macaca fascicularis; Mice, Nude; Prodrugs; Rats, Sprague-Dawley; Nitrogen Mustard Compounds; Aziridines; Dose-Response Relationship, Drug
PubMed: 38492211
DOI: 10.1002/bdd.2385 -
ACS Applied Materials & Interfaces Mar 2024Functional materials that can quickly absorb and degrade mustard gas are essential for chemical warfare emergency response kits. In this study, a fiber membrane with...
Functional materials that can quickly absorb and degrade mustard gas are essential for chemical warfare emergency response kits. In this study, a fiber membrane with excellent adsorption and catalytic degradation activity was developed by solution blow spinning polystyrene (PS)/polyurethane (PU) and hydrothermal in situ growth of a zirconium-based MOF (MOF-808). The mechanical properties of the PS/PU fibers were improved by adding a trimethylolpropane tris (2-methyl-1-aziridine propionate) (TTMA) cross-linking agent. Moreover, the C═O bonds in TTMA provided abundant growth sites for MOF-808 in the hydrothermal process, thereby greatly increasing the loading capacity. The fiber surface was completely covered with the MOF-808 particles within 24 h. The PS/PU/TTMA/MOF-808 fiber membrane was used for the catalytic degradation of 2-chloroethyl ethyl sulfide (CEES). The degradation efficiency reached 97.7% after 72 h, indicating its great application potential in emergency wiping cloths for mustard gas adsorption and degradation.
PubMed: 38488122
DOI: 10.1021/acsami.4c00036 -
The Journal of Organic Chemistry Apr 2024We have disclosed a novel metal-free tandem cyclization reaction for the synthesis of 3-methyleneisoindolin-1-ones starting from ester-functionalized aziridines. This...
We have disclosed a novel metal-free tandem cyclization reaction for the synthesis of 3-methyleneisoindolin-1-ones starting from ester-functionalized aziridines. This strategy can be effectively promoted by DBU and carboxylic acids. Mechanistically, it involves sequential ring opening of aziridines with carboxylic acids, lactamization, and elimination of carboxylic acids.
PubMed: 38485493
DOI: 10.1021/acs.joc.3c02974