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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 -
Angewandte Chemie (International Ed. in... Jul 2023Polyethyleneimines find many applications in products such as detergents, adhesives, cosmetics, and for processes such as tissue culture, gene therapy, and CO capture....
Polyethyleneimines find many applications in products such as detergents, adhesives, cosmetics, and for processes such as tissue culture, gene therapy, and CO capture. The current state-of-the-art technology for the production of the branched polyethyleneimines involves aziridine feedstock which is a highly toxic, volatile and mutagenic chemical and raises significant concern to human health and environment. We report here a novel method for the synthesis of branched polyethyleneimine derivative from ethylene glycol and ethylenediamine which are much safer, environmentally benign, commercially available and potentially renewable feedstock. The polymerisation reaction is catalysed by a complex of an earth-abundant metal, manganese and liberates H O as the only by-product. Our mechanistic studies using a combination of DFT computation and experiment suggest that the reaction proceeds by the formation and subsequent hydrogenation of imine intermediates.
PubMed: 37195140
DOI: 10.1002/anie.202306655 -
Medical Oncology (Northwood, London,... Jun 2024Treating metastatic malignancies to the central nervous system (CNS) is challenging because many drugs cannot cross the blood-brain-barrier (BBB). Direct intrathecal... (Review)
Review
Treating metastatic malignancies to the central nervous system (CNS) is challenging because many drugs cannot cross the blood-brain-barrier (BBB). Direct intrathecal (IT) drug administration into the cerebrospinal fluid (CSF) is a strategy to overcome this problem. Thiotepa has effective CNS penetration but its popularity has waned over the last two decades due to concerns about its efficacy and potential systemic toxicity. This review evaluates the available evidence for the use of IT thiotepa in hematologic malignancies and non-CNS solid tumors with leptomeningeal disease metastases (LMD). Our search shows that IT thiotepa is a reasonable alternative in hematologic malignancies and LMD due to solid organ malignancies. This suggests a potential role of IT thiotepa in second-or third-line treatment or a substitute role in cases of drug-shortages and adverse effects with other agents. Future research should focus on rigorous comparative trials to establish its definitive role in the evolving landscape of CNS-directed chemotherapy.
Topics: Humans; Thiotepa; Injections, Spinal; Central Nervous System Neoplasms; Antineoplastic Agents, Alkylating; Hematologic Neoplasms; Meningeal Neoplasms
PubMed: 38884819
DOI: 10.1007/s12032-024-02401-w -
Chemistry (Weinheim An Der Bergstrasse,... Aug 2023The discovery of new catalytic applications for metals remains an important goal in organic synthesis. If a catalyst has multiple functions, such as inducing bond...
The discovery of new catalytic applications for metals remains an important goal in organic synthesis. If a catalyst has multiple functions, such as inducing bond cleavage and formation, it can streamline multi-step transformations. Herein, the Cu-catalyzed synthesis of imidazolidine through heterocyclic recombination between aziridine and diazetidine is reported. Mechanistically, Cu catalyzes the conversion of diazetidine into the corresponding imine, which then reacts with aziridine to form imidazolidine. The scope is sufficiently wide to form various imidazolidines, as many functional groups are compatible with the reaction conditions.
PubMed: 37188644
DOI: 10.1002/chem.202301071 -
Bone Marrow Transplantation Sep 2023
Treosulfan, thiotepa and fludarabine conditioning regimen prior to first allogeneic stem cell transplantation in acute myeloid leukemia and high-risk myelodysplastic syndromes: a single center experience.
Topics: Humans; Thiotepa; Busulfan; Hematopoietic Stem Cell Transplantation; Vidarabine; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Transplantation Conditioning; Graft vs Host Disease
PubMed: 37355712
DOI: 10.1038/s41409-023-02023-2 -
Organic Letters Aug 2023Herein we report a nickel-catalyzed regioselective cross-electrophile ring opening reaction of sulfonyl-protected aziridines with trifluoromethyl-substituted alkenes as...
Herein we report a nickel-catalyzed regioselective cross-electrophile ring opening reaction of sulfonyl-protected aziridines with trifluoromethyl-substituted alkenes as the -difluoroallylating agents, providing a new and efficient entry to prepare -difluorobishomoallylic sulfonamides. Moreover, the scaffold of 6-fluoro-1,2,3,4-tetrahydropyridine can be constructed starting from the ring opening products via NaH-mediated intramolecular defluorinative nucleophilic vinylic substitution.
PubMed: 37503939
DOI: 10.1021/acs.orglett.3c01973 -
Transplantation and Cellular Therapy Jan 2024Reduced-intensity conditioning (RIC) and nonmyeloablative (NMA) conditioning are preferred for patients with non-Hodgkin lymphoma (NHL) undergoing allogeneic...
Reduced-intensity conditioning (RIC) and nonmyeloablative (NMA) conditioning are preferred for patients with non-Hodgkin lymphoma (NHL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT). Although prior studies have suggested that higher-intensity regimens in RIC-NMA conditioning are associated with inferior outcomes in patients with NHL, the optimal conditioning regimen remains unknown. We performed a retrospective single-center analysis to determine outcomes of adult patients with B cell and T cell NHL who underwent allo-HCT and received either RIC or NMA conditioning between March 2008 and December 2019. RIC regimens included fludarabine-cyclophosphamide-thiotepa-4 Gy-total body irradiation (Flu-Cy-TT-4Gy-TBI), fludarabine-melphalan (Flu-Mel), fludarabine-cyclophosphamide-4 Gy-total body irradiation (Flu-Cy-4Gy-TBI), and fludarabine-busulfan-4 (Flu-Bu-4). The NMA regimen comprised fludarabine-cyclophosphamide-2 Gy-total body irradiation (Flu-Cy-2Gy-TBI). The primary outcome was overall survival (OS); secondary outcomes included progression-free survival (PFS), nonrelapse mortality (NRM), and the incidence of acute and chronic graft-versus-host-disease (GVHD). Of 279 transplants recipients (median age, 58 years), 110 received RIC (55% Flu-Mel, 38% Flu-Cy-TT-4Gy-TBI, 6% Flu-Bu-4, 1% Flu-Cy-4Gy-TBI) and 169 received NMA conditioning with Flu-Cy-2Gy-TBI. With a median of 64 months of follow-up post-allo-HCT, there was no significant difference in OS between the NMA and RIC groups (median, not reached [NR] versus 103 months; P = .1), and this was maintained on multivariable analysis. Similarly, after adjustment for all independently significant covariates (age, Karnofsky Performance Status [KPS], Hematopoietic Cell Transplantation Comorbidity Index [HCT-CI], and disease histology), the regression analysis showed no significant difference in PFS with RIC compared to NMA conditioning (hazard ratio [HR] 1.38; 95% confidence interval [CI], .92 to 2.09; P = .24). On univariable analysis, there was no significant difference in NRM between the RIC and NMA arms (100-day estimate, 10.0% versus 1.8%; P = .5). After adjustment for age, ethnicity, KPS, HCT-CI, GVHD prophylaxis, and donor source, RIC conditioning was associated with a significantly higher incidence of NRM compared to NMA conditioning (HR, 2.61; 95% CI, 1.04 to 6.52; P = .039). On multivariable analysis, compared with the NMA arm, the RIC arm had higher rates of grade II-IV (HR, 2.25; 95% CI, 1.31 to 3.86; P = .002) and grade III-IV acute GVHD (HR, 5.62; 95% CI, 2.03 to 15.6; P < .001). The findings of this study suggest that NMA conditioning with Flu-Cy-TBI-2Gy may be considered over more intensive RIC regimens for patients with NHL undergoing allo-HCT.
Topics: Adult; Humans; Middle Aged; Retrospective Studies; Transplantation, Homologous; Survival Analysis; Hematopoietic Stem Cell Transplantation; Lymphoma, Non-Hodgkin; Cyclophosphamide; Graft vs Host Disease; Busulfan; Thiotepa
PubMed: 37788792
DOI: 10.1016/j.jtct.2023.09.022 -
Organic Letters Jul 2023Enantioselective dearomative cycloadditions of 4-nitroisoxazoles with vinylethylene carbonate () proceeded in the presence of Pd(dba) and ()-DTBM-SEGPHOS to give the...
Enantioselective dearomative cycloadditions of 4-nitroisoxazoles with vinylethylene carbonate () proceeded in the presence of Pd(dba) and ()-DTBM-SEGPHOS to give the corresponding bicyclic isoxazolines and in good to high yields with excellent enantioselectivities (≤99% ee). This synthetic approach could be applied to -tosyl vinyl aziridine and 2-methylidenetrimethylene carbonate. Further transformations of the resulting cycloadducts and yielded not only its derivatives and but also the novel tetracyclic skeleton .
PubMed: 37358472
DOI: 10.1021/acs.orglett.3c01324 -
Journal of the American Society For... Sep 2023Characterization of nonpolar lipids is crucial due to their essential biological functions and ability to exist in various isomeric forms. In this study, we introduce...
Characterization of nonpolar lipids is crucial due to their essential biological functions and ability to exist in various isomeric forms. In this study, we introduce the N-H aziridination method to target carbon-carbon double bonds (C═C bonds) in nonpolar sterol lipids. The resulting fragments are readily dissociated upon collision-induced dissociation, generating specific fragment ions for C═C bond position determination and fingerprint fragments for backbone characterization. This method significantly enhances lipid ionization efficiency, thereby improving the sensitivity and accuracy of nonpolar lipid analysis. We demonstrated that aziridination of sterols leads to distinctive fragmentation pathways for chain and ring C═C bonds, enabling the identification of sterol isomers such as desmosterol and 7-dehydrocholesterol. Furthermore, aziridination can assist in identifying the sterol backbone by providing fingerprint tandem mass spectra. We also demonstrated the quantitative capacity of this approach with a limit of detection of 10 nM in the solvent mixture of methanol and water. To test the feasibility of this method in complex biological samples, we used mouse prostate cancerous tissues and found significant differences in nonpolar lipid profiles between healthy and cancerous samples. The high efficiency and specificity of aziridination-assisted mass spectrometric analysis, as well as its quantitative analysis ability, make it highly suitable for broad applications in nonpolar lipid research.
Topics: Male; Mice; Animals; Sterols; Isomerism; Tandem Mass Spectrometry; Phytosterols; Carbon; Spectrometry, Mass, Electrospray Ionization
PubMed: 37523498
DOI: 10.1021/jasms.3c00161 -
Journal of Natural Medicines Jan 2024Epoxides, aziridines, and cyclopropanes are found in various medicinal natural products, including polyketides, terpenes, peptides, and alkaloids. Many classes of... (Review)
Review
Epoxides, aziridines, and cyclopropanes are found in various medicinal natural products, including polyketides, terpenes, peptides, and alkaloids. Many classes of biosynthetic enzymes are involved in constructing these ring structures during their biosynthesis. This review summarizes our current knowledge regarding how α-ketoglutarate-dependent nonheme iron enzymes catalyze the formation of epoxides, aziridines, and cyclopropanes in nature, with a focus on enzyme mechanisms.
Topics: Iron; Ketoglutaric Acids; Catalysis; Cyclopropanes; Aziridines; Epoxy Compounds
PubMed: 37980694
DOI: 10.1007/s11418-023-01760-4