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Redox Biology Jun 2024Protein disulfide isomerases (PDIs) are involved in many intracellular and extracellular processes, including cell adhesion and cytoskeletal reorganisation, but their...
Protein disulfide isomerases (PDIs) are involved in many intracellular and extracellular processes, including cell adhesion and cytoskeletal reorganisation, but their contribution to the regulation of fenestrations in liver sinusoidal endothelial cells (LSECs) remains unknown. Given that fenestrations are supported on a cytoskeleton scaffold, this study aimed to investigate whether endothelial PDIs regulate fenestration dynamics in primary mouse LSECs. PDIA3 and PDIA1 were found to be the most abundant among PDI isoforms in LSECs. Taking advantage of atomic force microscopy, the effects of PDIA1 or PDIA3 inhibition on the fenestrations in LSECs were investigated using a classic PDIA1 inhibitor (bepristat) and novel aromatic N-sulfonamides of aziridine-2-carboxylic acid derivatives as PDIA1 (C-3389) or PDIA3 (C-3399) inhibitors. The effect of PDIA1 inhibition on liver perfusion was studied in vivo using dynamic contrast-enhanced magnetic resonance imaging. Additionally, PDIA1 inhibitors were examined in vitro in LSECs for effects on adhesion, cytoskeleton organisation, bioenergetics, and viability. Inhibition of PDIA1 with bepristat or C-3389 significantly reduced the number of fenestrations in LSECs, while inhibition of PDIA3 with C-3399 had no effect. Moreover, the blocking of free thiols by the cell-penetrating N-ethylmaleimide, but not by the non-cell-penetrating 4-chloromercuribenzenesulfonate, resulted in LSEC defenestration. Inhibition of PDIA1 did not affect LSEC adhesion, viability, and bioenergetics, nor did it induce a clear-cut rearrangement of the cytoskeleton. However, PDIA1-dependent defenestration was reversed by cytochalasin B, a known fenestration stimulator, pointing to the preserved ability of LSECs to form new pores. Importantly, systemic inhibition of PDIA1 in vivo affected intra-parenchymal uptake of contrast agent in mice consistent with LSEC defenestration. These results revealed the role of intracellular PDIA1 in the regulation of fenestration dynamics in LSECs, and in maintaining hepatic sinusoid homeostasis.
Topics: Animals; Male; Mice; Cell Adhesion; Cells, Cultured; Cytoskeleton; Endothelial Cells; Enzyme Inhibitors; Liver; Protein Disulfide-Isomerases
PubMed: 38669864
DOI: 10.1016/j.redox.2024.103162 -
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 -
Frontiers in Chemistry 2024
PubMed: 38800579
DOI: 10.3389/fchem.2024.1421449 -
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 -
Journal of Inorganic Biochemistry Jul 2024The solvated iron(II) salt [Fe(NCMe)](BF) (Me = methyl) is shown to be a bifunctional catalyst with respect to aziridination of styrene. The salt serves as an active...
The solvated iron(II) salt [Fe(NCMe)](BF) (Me = methyl) is shown to be a bifunctional catalyst with respect to aziridination of styrene. The salt serves as an active catalyst for nitrene transfer from PhINTs to styrene to form 2-phenyl-N-tosylaziridine (Ph = phenyl; Ts = tosyl, -S{O}-p-CHMe). The iron(II) salt also acts as a Lewis acid in non-coordinating CHCl solution, to catalyze heterolytic CN bond cleavage of the aziridine and insertion of dipolarophiles. The 1,3-zwitterionic intermediate is presumably supported by interaction of the metal dication with the anion, and by resonance stabilization of the carbocation. Nucleophilic dipolarophiles then insert to give a five-membered heterocyclic ring. The result is a two-step cycloaddition, formally [2 + 1 + 2], that is typically regiospecific, but not stereospecific. This reaction mechanism was confirmed by conducting a series of one-step, [3 + 2] additions of unsaturated molecules into pre-formed 2-phenyl-N-tosylaziridine, also catalyzed by [Fe(NCMe)](BF). Relevant substrates include styrenes, carbonyl compounds and alkynes. These yield five-membered heterocylic rings, including pyrrolidines, oxazolidines and dihydropyrroles, respectively. The reaction scope appears limited only by the barrier to formation of the dipolar intermediate, and by the nucleophilicity of the captured dipolarophile. The bifunctionality of an inexpensive, earth-abundant and non-toxic catalyst suggests a general strategy for one-pot construction of heterocyclic rings, as demonstrated specifically for pyrrolidine ring formation.
Topics: Aziridines; Catalysis; Styrene; Ferrous Compounds; Heterocyclic Compounds; Cycloaddition Reaction; Imines
PubMed: 38678911
DOI: 10.1016/j.jinorgbio.2024.112551 -
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 -
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 -
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 -
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 -
Journal of the American Chemical Society Jan 2024Chiral aziridines are important structural motifs found in natural products and various target molecules. They serve as versatile building blocks for the synthesis of...
Chiral aziridines are important structural motifs found in natural products and various target molecules. They serve as versatile building blocks for the synthesis of chiral amines. While advances in catalyst design have enabled robust methods for enantioselective aziridination of activated olefins, simple and abundant alkyl-substituted olefins pose a significant challenge. In this work, we introduce a novel approach utilizing a planar chiral rhodium indenyl catalyst to facilitate the enantioselective aziridination of unactivated alkenes. This transformation exhibits a remarkable degree of functional group tolerance and displays excellent chemoselectivity favoring unactivated alkenes over their activated counterparts, delivering a wide range of enantioenriched high-value chiral aziridines. Computational studies unveil a stepwise aziridination mechanism in which alkene migratory insertion plays a central role. This process results in the formation of a strained four-membered metallacycle and serves as both the enantio- and rate-determining steps in the overall reaction.
PubMed: 38170978
DOI: 10.1021/jacs.3c10637