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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 -
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 -
Oncotarget Mar 2024ABT199/venetoclax, an inhibitor of the pro-survival BCL-2 protein, has improved AML treatment. Its efficacy in hematopoietic stem cell transplantation (HSCT), when...
ABT199/venetoclax, an inhibitor of the pro-survival BCL-2 protein, has improved AML treatment. Its efficacy in hematopoietic stem cell transplantation (HSCT), when combined with other chemotherapeutic drugs, has not been thoroughly investigated. The present study demonstrates the synergistic cytotoxicity of ABT199/venetoclax with the DNA alkylator thiotepa (Thio) in AML cells. Cleavage of Caspase 3, PARP1 and HSP90, as well as increased Annexin V positivity, suggest potent activation of apoptosis by this two-drug combination; increased levels of γ-H2AX, P-CHK1 (S317), P-CHK2 (S19) and P-SMC1 (S957) indicate an enhanced DNA damage response. Likewise, the increased level of P-SAPK/JNK (T183/Y185) and decreased P-PI3Kp85 (Y458) suggest enhanced activation of stress signaling pathways. These molecular readouts were synergistically enhanced when ABT199/venetoclax and Thio were combined with fludarabine, cladribine and busulfan. The five-drug combination decreased the levels of BCL-2, BCL-xL and MCL-1, suggesting its potential clinical relevance in overcoming ABT199/venetoclax resistance. Moreover, this combination is active against P53-negative and FLT3-ITD-positive cell lines. Enhanced activation of apoptosis was observed in leukemia patient-derived cell samples exposed to the five-drug combination, suggesting a clinical relevance. The results provide a rationale for clinical trials using these two- and five-drug combinations as part of a conditioning regimen for AML patients undergoing HSCT.
Topics: Humans; Busulfan; Thiotepa; Cladribine; Leukemia, Myeloid, Acute; Bridged Bicyclo Compounds, Heterocyclic; Proto-Oncogene Proteins c-bcl-2; Drug Combinations; Cell Line, Tumor; Apoptosis; Sulfonamides; Vidarabine
PubMed: 38484153
DOI: 10.18632/oncotarget.28563 -
Angewandte Chemie (International Ed. in... May 2024Since Friedrich Wöhler's groundbreaking synthesis of urea in 1828, organic synthesis over the past two centuries has predominantly relied on the exploration and... (Review)
Review
Since Friedrich Wöhler's groundbreaking synthesis of urea in 1828, organic synthesis over the past two centuries has predominantly relied on the exploration and utilization of chemical reactions rooted in two-electron heterolytic ionic chemistry. While one-electron homolytic radical chemistry is both rich in fundamental reactivities and attractive with practical advantages, the synthetic application of radical reactions has been long hampered by the formidable challenges associated with the control over reactivity and selectivity of high-energy radical intermediates. To fully harness the untapped potential of radical chemistry for organic synthesis, there is a pressing need to formulate radically different concepts and broadly applicable strategies to address these outstanding issues. In pursuit of this objective, researchers have been actively developing metalloradical catalysis (MRC) as a comprehensive framework to guide the design of general approaches for controlling over reactivity and stereoselectivity of homolytic radical reactions. Essentially, MRC exploits the metal-centered radicals present in open-shell metal complexes as one-electron catalysts for homolytic activation of substrates to generate metal-entangled organic radicals as the key intermediates to govern the reaction pathway and stereochemical course of subsequent catalytic radical processes. Different from the conventional two-electron catalysis by transition metal complexes, MRC operates through one-electron chemistry utilizing stepwise radical mechanisms.
PubMed: 38472114
DOI: 10.1002/anie.202320243 -
Journal of Clinical and Experimental... Mar 2024Primary testicular lymphoma (PTL) frequently relapses in the central nervous system (CNS) despite prophylactic intrathecal chemotherapy, and the outcome for CNS...
Successful treatment of isolated central nervous system recurrence of primary testicular lymphoma by autologous stem cell transplantation using a conditioning regimen of thiotepa and busulfan.
Primary testicular lymphoma (PTL) frequently relapses in the central nervous system (CNS) despite prophylactic intrathecal chemotherapy, and the outcome for CNS recurrence of PTL is very poor. We report a case of isolated CNS recurrence of bilateral PTL. Our patient achieved complete response (CR) after rituximab-combination chemotherapy for PTL. Approximately five years later, isolated CNS recurrence of PTL occurred. Our patient achieved CR again after high-dose methotrexate therapy and autologous stem cell transplantation (ASCT) with a conditioning regimen of thiotepa and busulfan as a consolidation therapy. The secondary failure of platelet recovery, probably caused by busulfan, occurred after the platelet engraftment. Our patient has remained in CR for over three years. The treatment strategy for CNS recurrence of PTL is mainly whole-brain radiotherapy or high-dose methotrexate-based chemotherapy; however, CNS recurrence of PTL may occur again even after achieving CR. ASCT with a conditioning regimen of thiotepa and busulfan is the optimal consolidation therapy for secondary CNS lymphoma. To the best of our knowledge, this is the second reported case of a patient with isolated CNS recurrence of PTL successfully treated by ASCT with a conditioning regimen of thiotepa and busulfan as a consolidation therapy.
Topics: Humans; Thiotepa; Hematopoietic Stem Cell Transplantation; Busulfan; Methotrexate; Transplantation, Autologous; Antineoplastic Combined Chemotherapy Protocols; Neoplasm Recurrence, Local; Lymphoma; Central Nervous System; Combined Modality Therapy; Stem Cell Transplantation; Transplantation Conditioning
PubMed: 38417873
DOI: 10.3960/jslrt.23039 -
Polymers Feb 2024Commercially available poly(lactic acid) exhibits poor hydrolytic stability, which makes it impossible for use in durable applications. Therefore, a novel hydrolysis...
Commercially available poly(lactic acid) exhibits poor hydrolytic stability, which makes it impossible for use in durable applications. Therefore, a novel hydrolysis inhibitor based on an aziridine derivative as well as a novel stabilizer composition, containing an aziridine derivative and an acid scavenger, were investigated to improve the hydrolytic stability. To evaluate the stabilizing effect, the melt volume rate (MVR) and molecular weight were monitored during an accelerated hydrolytic aging in water at elevated temperatures. Temperatures were selected according to the glass transition temperature (~60 °C) of PLA. It was shown that the novel hydrolysis inhibitor as well as the novel stabilizer composition exhibited excellent performance during hydrolytic aging, exceeding commercially available alternatives, e.g., polymeric carbodiimides. A molecular weight analysis resulted in a molecular weight decrease of only 10% during approximately 850 h and up to 20% after 1200 h of hydrolytic aging, whereas poly(lactic acid) stabilized with a commercial polycarbodiimide revealed comparable molecular weight reductions after only 300 h. Furthermore, the stabilization mechanism of the aziridine derivative alone, as well as in the synergistic combination with the acid scavenger (calcium hydrotalcite), was investigated using nuclear magnetic resonance (NMR) spectroscopy. In addition to an improved hydrolytic stability, the thermal properties were also enhanced compared to polymeric carbodiimides.
PubMed: 38399884
DOI: 10.3390/polym16040506 -
The Journal of Organic Chemistry Mar 2024Aziridines are important structural motifs and intermediates, and several synthetic strategies for the direct aziridination of alkenes have been introduced. However,...
Aziridines are important structural motifs and intermediates, and several synthetic strategies for the direct aziridination of alkenes have been introduced. However, many of these strategies require an excess of activated alkene, suffer from competing side-reactions, have limited functional group tolerance, or involve precious transition metal-based catalysts. Herein, we demonstrate the direct aziridination of alkenes by combining sulfonyl azides as a triplet nitrene source with a catalytic amount of an organic dye functioning as photosensitizer. We show how the nature of the sulfonyl azide, in combination with the triplet-excited state energy of the photosensitizer, affects the aziridination yield and provide a mechanistic rationale to account for the observed dependence of the reaction yield on the nature of the organic dye and sulfonyl azide reagents. The optimized reaction conditions enable the aziridination of structurally diverse and complex alkenes, carrying various functional groups, with the alkene as the limiting reagent.
PubMed: 38358354
DOI: 10.1021/acs.joc.3c02709 -
Journal of the American Chemical Society Feb 2024The first enantioselective total synthesis of (-)-hunterine A is disclosed. Our strategy employs a catalytic asymmetric desymmetrization of a symmetrical diketone and...
The first enantioselective total synthesis of (-)-hunterine A is disclosed. Our strategy employs a catalytic asymmetric desymmetrization of a symmetrical diketone and subsequent Beckmann rearrangement to construct a 5,6-α-aminoketone. A convergent 1,2-addition joins a vinyl dianion nucleophile and the enantioenriched ketone. The endgame of the synthesis features an aza-Cope/Mannich reaction and azide-olefin dipolar cycloaddition to complete the pentacyclic ring system. The synthesis is completed through a regioselective aziridine ring opening.
PubMed: 38346145
DOI: 10.1021/jacs.3c13590 -
The Journal of Organic Chemistry Mar 2024Sp-enriched small molecules play a critical role in developing drug candidates. While designing analogues with greater sp character, a methodology utilizing a less...
Sp-enriched small molecules play a critical role in developing drug candidates. While designing analogues with greater sp character, a methodology utilizing a less explored cyclic-aziridine amide ring-opening reaction to generate sp-enriched scaffolds has been developed and reported. This methodology enables rapid access to substructures with higher fsp values, attracting greater attention within the past few decades. The reaction exhibits a wide reaction scope, featuring a highly sterically hindered phenolic ether, thiophenolic ethers, protected aniline formations, and aliphatic/heteroaromatic ring-containing aziridine amides as substrates. Additionally, this reaction provides access to congested tertiary ether formations through regioselective transformation, applicable to an extensive range of drug discovery targets, construction of complex small molecules, and natural product syntheses. The scaffolds developed show improved physicochemical properties.
PubMed: 38340064
DOI: 10.1021/acs.joc.3c02952 -
Angewandte Chemie (International Ed. in... Mar 2024This manuscript describes the development of alkyne addition to the aziridine moiety of aziridinoquinoxalines using dual Ir(III)/Cu(I) catalytic system under green...
This manuscript describes the development of alkyne addition to the aziridine moiety of aziridinoquinoxalines using dual Ir(III)/Cu(I) catalytic system under green light-emitting diode (LED) photolysis (λ =525 nm). This mild method features high levels of chemo- and regioselectivity and was used to generate 30 highly functionalized substituted dihydroquinoxalines in 36-98 % yield. This transformation was also carried asymmetrically using phthalazinamine-based chiral ligand to provide 9 chiral addition products in 96 : 4 to 86 : 14 e.r. The experimental and quantum chemical explorations of this reaction suggest a mechanism that involves Ir(III)-catalyzed triplet energy transfer followed by a ring-opening reaction ultimately leading to the formation of azomethine ylide intermediates. These azomethine intermediates undergo sequential protonation/copper(I) acetylide addition to provide the products.
PubMed: 38267370
DOI: 10.1002/anie.202318876