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Journal of Enzyme Inhibition and... Dec 2023In this study, we report a series of newly synthesised sulphonamides of aziridine-2-carboxylic acid (Az-COOH) ester and amide analogues as potent protein disulphide...
In this study, we report a series of newly synthesised sulphonamides of aziridine-2-carboxylic acid (Az-COOH) ester and amide analogues as potent protein disulphide isomerase (PDI, EC 5.3.4.1) inhibitors. The inhibitory activity on PDI was determined against recombinant human PDIA1 and PDIA3 proteins using an insulin reduction assay. These compounds in low micromolar to low nanomolar concentrations showed the effective inhibitory properties of PDIA1 with weaker effects on PDIA3. Complexes of N- and N,C- uniformly labelled recombinant human PDIA1a with two PDIA1 inhibitors were produced and investigated by a protein nuclear magnetic resonance (NMR) spectroscopy. It was found that both C53 and C56 of the PDIA1 enzyme were involved in covalent binding. Finally, in a range of pharmacological studies, we demonstrated that investigated compounds displayed anti-cancer and anti-thrombotic activity. These findings demonstrate that sulphonamides of Az-COOH derivatives are promising candidates for the development of novel anti-cancer and anti-thrombotic agents.
Topics: Humans; Aziridines; Protein Disulfide-Isomerases; Sulfonamides
PubMed: 37070480
DOI: 10.1080/14756366.2022.2158187 -
The Journal of Organic Chemistry Jul 2023We have developed a highly stereospecific cyclization of aziridine silanols into 1'-amino-tetrahydrofurans. Our protocol of stirring a substrate with 10 mol % Sc (OTf)...
We have developed a highly stereospecific cyclization of aziridine silanols into 1'-amino-tetrahydrofurans. Our protocol of stirring a substrate with 10 mol % Sc (OTf) and 1 equivalent of NaHCO in CHCl is mild and compatible with a range of activating aziridine -substituents (including tosylates, mesylates, and carbamates) and functional groups on the alkyl chains (including substituted aryl rings, alkyl bromides, and alkyl ethers). In all cases examined, di-substituted aziridine silanols give products with an configuration; conversely, di-substituted aziridine silanols give products with a configuration. While literature syntheses of 1'-amino-tetrahydrofurans exist, only one example, contemporaneous with our work, uses a similar cyclization for their construction. Control experiments demonstrate that, for this transformation, the silanol is not particularly privileged, and a variety of protecting groups on the alcohol (including other silicon protecting groups, benzyl ethers, and MOM ethers) are compatible with product formation.
Topics: Furans; Stereoisomerism; Ethers; Aziridines
PubMed: 37253098
DOI: 10.1021/acs.joc.3c00763 -
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 -
Molecules (Basel, Switzerland) Jul 2023The efficient one-pot halofluorination of a -enaminophosphonate/-iminophosphonate tautomeric mixture resulting in ,-halofluorinated -iminophosphonates is reported....
The efficient one-pot halofluorination of a -enaminophosphonate/-iminophosphonate tautomeric mixture resulting in ,-halofluorinated -iminophosphonates is reported. Subsequent imine reduction gave the corresponding -aminophosphonates as a racemic mixture or with high diastereoselectivity. The proposed protocol is the first example of a synthesis of -inactivated aziridines substituted by a fluorine and phosphonate moiety on the same carbon atom. Based on spectroscopic and theoretical studies, we determined the / geometry of the resulting fluorinated aziridine-2-phosphonate. Our procedure, involving the reduction of -fluoroaziridine mixture , allows us to isolate chiral aziridines as well as aziridines that do not contain a fluorine atom. We also investigated the influence of the fluorine atom on the reactivity of aziridine through an acid-catalyzed regioselective ring-opening reaction. The results of DFT calculations, at the PCM/ωB97x-D/def2-TZVPD level of theory, are in good agreement with the experiments. The transition states of the S2 intramolecular cyclization of vicinal haloamines have been modeled.
PubMed: 37513451
DOI: 10.3390/molecules28145579 -
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 -
ACS Chemical Biology Dec 2023GH127 and GH146 microorganismal retaining β-l-arabinofuranosidases, expressed by human gut microbiomes, feature an atypical catalytic domain and an unusual mechanism of...
GH127 and GH146 microorganismal retaining β-l-arabinofuranosidases, expressed by human gut microbiomes, feature an atypical catalytic domain and an unusual mechanism of action. We recently reported that both GH146 and HypBA1 are inhibited by β-l-furanosyl cyclophellitol epoxide, supporting the action of a zinc-coordinated cysteine as a catalytic nucleophile, where in most retaining GH families, an aspartate or glutamate is employed. This work presents a panel of β-l-furanosyl cyclophellitol epoxides and aziridines as mechanism-based GH146/HypBA1 inhibitors and activity-based probes. The β-l-furanosyl cyclophellitol aziridines both inhibit and label β-l-arabinofuranosidase efficiently (however with different activities), whereas the epoxide-derived probes favor GH146 over HypBA1. These findings are accompanied by X-ray structural analysis of the unmodified β-l-furanosyl cyclophellitol aziridine in complex with both isozymes, which were shown to react by nucleophilic opening of the aziridine, at the pseudoanomeric carbon, by the active site cysteine nucleophile to form a stable thioether bond. Altogether, our activity-based probes may serve as chemical tools for the detection and identification of low-abundance β-l-arabinofuranosidases in complex biological samples.
Topics: Humans; Cysteine; Glycoside Hydrolases; Aziridines; Epoxy Compounds
PubMed: 38051515
DOI: 10.1021/acschembio.3c00558 -
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 -
Chemical Science Nov 2023The introduction of nitrogen atoms into small molecules is of fundamental importance and it is vital that ever more efficient and selective methods for achieving this... (Review)
Review
The introduction of nitrogen atoms into small molecules is of fundamental importance and it is vital that ever more efficient and selective methods for achieving this are developed. With this aim, the potential of nitrene chemistry has long been appreciated but its application has been constrained by the extreme reactivity of these labile species. This liability however can be attenuated by complexation with a transition metal and the resulting metal nitrenoids have unique and highly versatile reactivity which includes the amination of certain types of aliphatic C-H bonds as well as reactions with alkenes to afford aziridines. At least one new chiral centre is typically formed in these processes and the development of catalysts to exert control over enantioselectivity in nitrenoid-mediated amination has become a growing area of research, particularly over the past two decades. Compared with some synthetic methods, metal nitrenoid chemistry is notable in that chemists can draw from a diverse array of metals and catalysts , ranging from metal-ligand complexes, bearing a variety of ligand types, bio-inspired metalloporphyrins, all the way through to, very recently, engineered enzymes themselves. In the latter category in particular, rapid progress is being made, the rate of which suggests that this approach may be instrumental in addressing some of the outstanding challenges in the field. This review covers key developments and strategies that have shaped the field, in addition to the latest advances, up until September 2023.
PubMed: 38020383
DOI: 10.1039/d3sc04661c