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International Journal of Molecular... Nov 2023The reactions of alkenes with phenyl--triflylimino-λ-iodane PhI=NTf () have been studied in different conditions. In methylene chloride, in the presence of...
The reactions of alkenes with phenyl--triflylimino-λ-iodane PhI=NTf () have been studied in different conditions. In methylene chloride, in the presence of -halosuccinimides, the products of mono and bis-triflamidation were obtained. In MeCN, the product of bromotriflamidation (with NBS) with solvent interception or of bis-triflamidation (with NIS) is formed. The reaction with -stilbene in acetonitrile with NBS gave rise to cyclization to 2-methyl-4,5-diphenyl-1-triflyl-4,5-dihydro-1-imidazole. In contrast, with NIS as an oxidant, both in CHCl and MeCN, the major product was 2,3-diphenyl-1-triflylaziridine formed in good yield. With NBS, aziridine is also formed but as a minor product, the major one being a mixture of diastereomers of the product of bromotriflamidation. The reaction of compound with vinylcyclohexane in methylene chloride affords the mixtures of regioisomers of the products of halotriflamidation, whereas in acetonitrile, the products of solvent interception and cyclization to the imidazoline are formed. A mechanism explaining the formation of all isolated products is proposed.
Topics: Oxidants; Molecular Structure; Solvents; Alkenes; Methylene Chloride; Acetonitriles
PubMed: 37958930
DOI: 10.3390/ijms242115947 -
Frontiers in Chemistry 2023Aziridine had different regioselective ring openings depending on the functional group of its alkyl substituent. In the case of the alkyl group bearing γ-ketone at the...
Aziridine had different regioselective ring openings depending on the functional group of its alkyl substituent. In the case of the alkyl group bearing γ-ketone at the C2 substituent of aziridine, the ring opening by the hydroxy nucleophile from HO occurred by attacking the aziridine carbon at the C2 position. This reaction proceeded efficiently in the presence of CFCOH. Interestingly, the same starting aziridine ring bearing the alkyl substituent at the C2 position with the γ-silylated hydroxy group instead of γ-ketone led to the ring-opening reaction by the same oxygen nucleophile at the unsubstituted C3 position, with the breakage of the bond between aziridine N1 nitrogen and carbon at C3. These reaction products were cyclized to afford substituted pyrrolidine and piperidine rings with representative examples of congeners of pseudoconhydrine and monomorine.
PubMed: 37927563
DOI: 10.3389/fchem.2023.1280633 -
The Journal of Organic Chemistry Nov 2023The ring opening of aziridines by pendant sulfamates is a viable strategy for the rapid preparation of vicinal diamines. Our reaction is compatible with both...
The ring opening of aziridines by pendant sulfamates is a viable strategy for the rapid preparation of vicinal diamines. Our reaction is compatible with both disubstituted - and -aziridines; unsubstituted, -alkyl, and -aryl sulfamates engage effectively. In all cases examined, the cyclization reaction is perfectly regioselective and stereospecific. Once activated, the product oxathiazinane heterocycles can be ring opened with a diverse range of nucleophiles.
PubMed: 37903411
DOI: 10.1021/acs.joc.3c01731 -
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 -
Journal of the American Chemical Society Nov 2023The arylation of 2-alkyl aziridines by nucleophilic ring-opening or transition-metal-catalyzed cross-coupling enables facile access to biologically relevant...
The arylation of 2-alkyl aziridines by nucleophilic ring-opening or transition-metal-catalyzed cross-coupling enables facile access to biologically relevant β-phenethylamine derivatives. However, both approaches largely favor C-C bond formation at the less-substituted carbon of the aziridine, thus enabling access to only linear products. Consequently, despite the attractive bond disconnection that it poses, the synthesis of branched arylated products from 2-alkyl aziridines has remained inaccessible. Herein, we address this long-standing challenge and report the first branched-selective cross-coupling of 2-alkyl aziridines with aryl iodides. This unique selectivity is enabled by a Ti/Ni dual-catalytic system. We demonstrate the robustness of the method by a twofold approach: an additive screening campaign to probe functional group tolerance and a feature-driven substrate scope to study the effect of the local steric and electronic profile of each coupling partner on reactivity. Furthermore, the diversity of this feature-driven substrate scope enabled the generation of predictive reactivity models that guided mechanistic understanding. Mechanistic studies demonstrated that the branched selectivity arises from a Ti-induced radical ring-opening of the aziridine.
PubMed: 37888947
DOI: 10.1021/jacs.3c08301 -
JACS Au Oct 2023Tropane alkaloids are an important class of biologically active small molecules characterized by their 8-azabicyclo[3.2.1]octane core. Because of their numerous...
Tropane alkaloids are an important class of biologically active small molecules characterized by their 8-azabicyclo[3.2.1]octane core. Because of their numerous medicinal applications, microbial biosynthesis and a variety of chemical syntheses have been designed for individual family members. However, current approaches are not amenable to late-stage structural diversification at N8, C3, C6, or C7, positions that are critical for modulating the biological properties of these molecules. Here, we describe a general approach to the synthesis of tropane alkaloids and their analogues that relies on the construction of the 8-azabicyclo[3.2.1]octane core through aziridination of a cycloheptadiene intermediate, followed by vinyl aziridine rearrangement. Using this strategy, we synthesized six tropane alkaloids and several analogues in only 5-7 steps. Given that the tropane alkaloid scopolamine has been reported to promote structural neuroplasticity and produce antidepressant effects, we tested five tropane-containing compounds for their ability to promote dendritic spine growth in cultured cortical neurons. We found that the orientation of the C3 substituent may play a role in the psychoplastogenic effects of tropane alkaloids. Our work provides a robust platform for producing tropane analogs for future structure-activity relationship studies.
PubMed: 37885569
DOI: 10.1021/jacsau.3c00472 -
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 -
Frontiers in Chemistry 2023Herein we report a copper-catalyzed synthesis of imidazolidine by employing the reaction of aziridine with imine. The reaction smoothly provided a diverse range of...
Herein we report a copper-catalyzed synthesis of imidazolidine by employing the reaction of aziridine with imine. The reaction smoothly provided a diverse range of 2-substituted imidazolidines with high compatibility with various functional groups. Moreover, during our investigation, we discovered that isocyanate also reacted with aziridine to yield substituted imidazolidinones efficiently. The versatility of these reactions was further demonstrated by their application in the synthesis of hybrid molecules derived from two pharmaceutical compounds. This approach opens new possibilities for the discovery of novel classes of bioactive molecules.
PubMed: 37841205
DOI: 10.3389/fchem.2023.1272034 -
Chemical Science Oct 2023Despite the myriad Cu-catalyzed nitrene transfer methodologies to form new C-N bonds (, amination, aziridination), the critical reaction intermediates have largely...
Despite the myriad Cu-catalyzed nitrene transfer methodologies to form new C-N bonds (, amination, aziridination), the critical reaction intermediates have largely eluded direct characterization due to their inherent reactivity. Herein, we report the synthesis of dipyrrin-supported Cu nitrenoid adducts, investigate their spectroscopic features, and probe their nitrene transfer chemistry through detailed mechanistic analyses. Treatment of the dipyrrin Cu complexes with substituted organoazides affords terminally ligated organoazide adducts with minimal activation of the azide unit as evidenced by vibrational spectroscopy and single crystal X-ray diffraction. The Cu nitrenoid, with an electronic structure most consistent with a triplet nitrene adduct of Cu, is accessed following geometric rearrangement of the azide adduct from κ-N terminal ligation to κ-N internal ligation with subsequent expulsion of N. For perfluorinated arylazides, stoichiometric and catalytic C-H amination and aziridination was observed. Mechanistic analysis employing substrate competition reveals an enthalpically-controlled, electrophilic nitrene transfer for primary and secondary C-H bonds. Kinetic analyses for catalytic amination using tetrahydrofuran as a model substrate reveal pseudo-first order kinetics under relevant amination conditions with a first-order dependence on both Cu and organoazide. Activation parameters determined from Eyring analysis (Δ = 9.2(2) kcal mol, Δ = -42(2) cal mol K, Δ = 21.7(2) kcal mol) and parallel kinetic isotope effect measurements (1.10(2)) are consistent with rate-limiting Cu nitrenoid formation, followed by a proposed stepwise hydrogen-atom abstraction and rapid radical recombination to furnish the resulting C-N bond. The proposed mechanism and experimental analysis are further corroborated by density functional theory calculations. Multiconfigurational calculations provide insight into the electronic structure of the catalytically relevant Cu nitrene intermediates. The findings presented herein will assist in the development of future methodology for Cu-mediated C-N bond forming catalysis.
PubMed: 37829016
DOI: 10.1039/d3sc03641c -
Transplantation and Cellular Therapy Jan 2024Total body irradiation (TBI) at myeloablative doses is superior to chemotherapy-based regimens in young patients with acute lymphoblastic leukemia (ALL) undergoing...
Thiotepa-Based Regimens Are Valid Alternatives to Total Body Irradiation-Based Reduced-Intensity Conditioning Regimens in Patients with Acute Lymphoblastic Leukemia: A Retrospective Study on Behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.
Total body irradiation (TBI) at myeloablative doses is superior to chemotherapy-based regimens in young patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, in elderly and unfit patients, in whom reduced-intensity conditioning (RIC) regimens are preferred, whether a TBI-based or a chemotherapy-based approach is better is unexplored. Thiotepa can be used as part of ALL conditioning regimens. The current study aimed to compare transplantation outcomes after RIC with TBI-based or thiotepa-based regimens in patients with ALL. The study cohort comprised patients aged ≥40 years undergoing allo-HSCT for ALL in first complete remission between 2000 and 2020 who received an RIC regimen containing either TBI (4 to 6 Gy) or thiotepa. We identified a total of 265 patients, including 117 who received a TBI-based RIC regimen and 148 who received a thiotepa-based RIC regimen. Univariate analysis revealed no significant differences in the following transplantation outcomes for TBI versus thiotepa: relapse, 23% versus 28% (P = .24); nonrelapse mortality, 20% versus 26% (P = .61); leukemia-free survival, 57% versus 46% (P = .12); overall survival, 67% versus 56% (P = .18); graft-versus-host disease (GVHD]/relapse-free survival, 45% versus 38% (P = .21); grade II-IV acute GVHD, 30% in both groups (P = .84); grade III-IV acute GVHD, 9% versus 10% (P = .89). The sole exception was the incidence of chronic GVHD, which was higher in the recipients of TBI-based regimens (43% versus 29%; P = .03). However, multivariate analysis revealed no differences in transplantation outcomes between the 2 groups. In patients aged ≥40 years receiving RIC, use of a thiotepa-based regimen may represent a valid alternative to TBI-based regimens, as no differences were observed in the main transplantation outcomes.
Topics: Aged; Humans; Thiotepa; Retrospective Studies; Whole-Body Irradiation; Bone Marrow; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Acute Disease; Graft vs Host Disease
PubMed: 37816471
DOI: 10.1016/j.jtct.2023.09.028