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RSC Advances May 2024Cyclic -sulfonyl aldimines are well-known aza-[2]-synthons for various [2 + ] annulation reactions. Herein we describe a novel base mediated [2 + 1] annulation and a...
Base mediated aza-[2 + 1] annulation and regioselective aziridine ring-opening cascade: mild synthesis of functionalized -amino ketones from cyclic -sulfonyl aldimines and -carbonyl sulfonium salts.
Cyclic -sulfonyl aldimines are well-known aza-[2]-synthons for various [2 + ] annulation reactions. Herein we describe a novel base mediated [2 + 1] annulation and a regioselective aziridine ring-opening reaction cascade, which provides an efficient and distinct synthetic strategy from readily available cyclic -sulfonyl aldimines and -carbonyl sulfonium salts leading to -amino ketone derivatives through the corresponding fused tri-substituted aziridines. This one-pot, two-step process involves formation of C-C and C-N bonds and subsequent cleavage of a C-N bond. The features of the developed reaction include the use of mild reaction conditions, broad substrate scope, and excellent yields. The synthetic utility of this approach was demonstrated by gram-scale operation and further product derivatizations.
PubMed: 38808243
DOI: 10.1039/d4ra02817a -
Frontiers in Chemistry 2024
PubMed: 38800579
DOI: 10.3389/fchem.2024.1421449 -
Molecules (Basel, Switzerland) May 2024Breast cancer is associated with high mortality and morbidity rates. As about 20-30% of patients exhibiting ER-positive phenotype are resistant to hormonal treatment...
Lactic Acid Bacteria-Derived Postbiotics as Adjunctive Agents in Breast Cancer Treatment to Boost the Antineoplastic Effect of a Conventional Therapeutic Comprising Tamoxifen and a New Drug Candidate: An Aziridine-Hydrazide Hydrazone Derivative.
Breast cancer is associated with high mortality and morbidity rates. As about 20-30% of patients exhibiting ER-positive phenotype are resistant to hormonal treatment with the standard drug tamoxifen, finding new therapies is a necessity. Postbiotics, metabolites, and macromolecules isolated from probiotic bacteria cultures have been proven to have sufficient bioactivity to exert prohealth and anticancer effects, making them viable adjunctive agents for the treatment of various neoplasms, including breast cancer. In the current study, postbiotics derived from and cultures were assessed on an in vitro breast cancer model as potential adjunctive agents to therapy utilizing tamoxifen and a candidate aziridine-hydrazide hydrazone derivative drug. Cell viability and cell death processes, including apoptosis, were analyzed for neoplastic MCF-7 cells treated with postbiotics and synthetic compounds. Cell cycle progression and proliferation were analyzed by PI-based flow cytometry and Ki-67 immunostaining. Postbiotics decreased viability and triggered apoptosis in MCF-7, modestly affecting the cell cycle and showing a lack of negative impact on normal cell viability. Moreover, they enhanced the cytotoxic effect of tamoxifen and the new candidate drug toward MCF-7, accelerating apoptosis and the inhibition of proliferation. This illustrates postbiotics' potential as natural adjunctive agents supporting anticancer therapy based on synthetic drugs.
Topics: Humans; Tamoxifen; Breast Neoplasms; MCF-7 Cells; Female; Aziridines; Apoptosis; Cell Proliferation; Cell Survival; Hydrazones; Probiotics; Antineoplastic Agents; Cell Cycle
PubMed: 38792153
DOI: 10.3390/molecules29102292 -
Organic Process Research & Development May 2024A new and highly efficient continuous flow process is presented for the synthesis of aziridines via the thermal Baldwin rearrangement. The process was initially explored...
A new and highly efficient continuous flow process is presented for the synthesis of aziridines via the thermal Baldwin rearrangement. The process was initially explored using traditional batch synthesis techniques but suffered from moderate yields, long reaction times, and moderate diastereoselectivities. Here we demonstrate that the process can be greatly improved upon its transfer to continuous flow, which afforded the aziridine targets in high yields, short reaction times, and consistently high diastereoselectivities, with the high-throughput process rendering multigram quantities of product in short periods of time. In addition, flow processing extended the substrate scope including several examples that had failed in batch mode, thus demonstrating the value of this overlooked entry into valuable aziridine species.
PubMed: 38783852
DOI: 10.1021/acs.oprd.3c00213 -
Molecules (Basel, Switzerland) Apr 2024The chiral aziridine-containing vicinal iminophenol tridentate ligands (named salazins) are a class of readily prepared chiral ligands from enantiopure aziridines and...
The chiral aziridine-containing vicinal iminophenol tridentate ligands (named salazins) are a class of readily prepared chiral ligands from enantiopure aziridines and salicylaldehydes. Their scandium and yttrium triflate complexes show excellent reactivity and enantioselectivities in the catalytic asymmetric aldol condensation of electron-deficient aromatic aldehydes and ketones, including acetone and cycloalkanones. The stereoselectivity is rationalized to the strong π-stacking interaction between aromatic aldehydes and the vicinal iminophenol group in the chiral ligands.
PubMed: 38731454
DOI: 10.3390/molecules29091963 -
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 -
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 -
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 -
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