-
Organic Letters Aug 2022We present a unique strategy for the synthesis of vicinal amino alcohols. Ring opening of aziridines with pendant silanols is compatible with a range of substrates. To...
Ring Opening of Aziridines by Pendant Silanols Allows for Preparations of (±)-Clavaminol H, (±)-Des-Acetyl-Clavaminol H, (±)-Dihydrosphingosine, and (±)--Hexanoyldihydrosphingosine.
We present a unique strategy for the synthesis of vicinal amino alcohols. Ring opening of aziridines with pendant silanols is compatible with a range of substrates. To engage productively in ring opening, the aziridine must be at least mildly activated, and a variety of such -substituents are tolerated. The utility of this methodology is highlighted in facile preparations of the natural products (±)-Clavaminol H, (±)-dihydrosphingosine, and (±)--hexanoyldihydrosphingosine as well as a natural product analogue (±)-des-acetyl-Clavaminol H.
Topics: Aziridines; Ceramides; Molecular Structure; Silanes; Sphingosine; Stereoisomerism
PubMed: 35951966
DOI: 10.1021/acs.orglett.2c02496 -
Chemistry (Weinheim An Der Bergstrasse,... Oct 2022The development of small-molecule covalent inhibitors and probes continuously pushes the rapidly evolving field of chemical biology forward. A key element in these...
The development of small-molecule covalent inhibitors and probes continuously pushes the rapidly evolving field of chemical biology forward. A key element in these molecular tool compounds is the "electrophilic trap" that allows a covalent linkage with the target enzyme. The reactivity of this entity needs to be well balanced to effectively trap the desired enzyme, while not being attacked by off-target nucleophiles. Here we investigate the intrinsic reactivity of substrates containing a class of widely used electrophilic traps, the three-membered heterocycles with a nitrogen (aziridine), phosphorus (phosphirane), oxygen (epoxide) or sulfur atom (thiirane) as heteroatom. Using quantum chemical approaches, we studied the conformational flexibility and nucleophilic ring opening of a series of model substrates, in which these electrophilic traps are mounted on a cyclohexene scaffold (C H Y with Y=NH, PH, O, S). It was revealed that the activation energy of the ring opening does not necessarily follow the trend that is expected from C-Y leaving-group bond strength, but steeply decreases from Y=NH, to PH, to O, to S. We illustrate that the HOMO -LUMO interaction is an all-important factor for the observed reactivity. In addition, we show that the activation energy of aziridines and phosphiranes can be tuned far below that of the corresponding epoxides and thiiranes by the addition of proper electron-withdrawing ring substituents. Our results provide mechanistic insights to rationally tune the reactivity of this class of popular electrophilic traps and can guide the experimental design of covalent inhibitors and probes for enzymatic activity.
Topics: Aziridines; Epoxy Compounds; Nitrogen; Phosphorus; Cyclohexenes; Sulfur; Oxygen
PubMed: 35896443
DOI: 10.1002/chem.202201649 -
Chemical Science Jul 2022Imidyl and nitrene metal species play an important role in the -functionalisation of unreactive C-H bonds as well as the aziridination of olefines. We report on the...
Imidyl and nitrene metal species play an important role in the -functionalisation of unreactive C-H bonds as well as the aziridination of olefines. We report on the synthesis of the trigonal imido iron complexes [Fe(NMes)L] (L = -N{Dipp}SiMe); Dipp = 2,6-diisopropyl-phenyl; Mes = (2,4,6-trimethylphenyl) reaction of mesityl azide (MesN) with the linear iron precursors [FeL]. UV-vis-, EPR-, Fe Mössbauer spectroscopy, magnetometry, and computational methods suggest for the reduced form an electronic structure as a ferromagnetically coupled iron(ii) imidyl radical, whereas oxidation leads to mixed iron(iii) imidyl and electrophilic iron(ii) nitrene character. Reactivity studies show that both complexes are capable of H atom abstraction from C-H bonds. Further, the reduced form [Fe(NMes)L] reacts nucleophilically with CS by inserting into the imido iron bond, as well as electrophilically with CO under nitrene transfer. The neutral [Fe(NMes)L] complex shows enhanced electrophilic behavior as evidenced by nitrene transfer to a phosphine, yet in combination with an overall reduced reactivity.
PubMed: 35865905
DOI: 10.1039/d2sc01088g -
Proceedings of the National Academy of... Jul 2022Polymers possessing helical conformation in the solid state are in high demand. We report a helical peptide-polymer via the topochemical ene-azide cycloaddition (TEAC)...
Polymers possessing helical conformation in the solid state are in high demand. We report a helical peptide-polymer via the topochemical ene-azide cycloaddition (TEAC) polymerization. The molecules of the designed Gly-Phe-based dipeptide, decorated with ene and azide, assemble in its crystals as β-sheets and as supramolecular helices in two mutually perpendicular directions. While the NH…O H-bonding facilitates β-sheet-like stacking along one direction, weak CH…N H-bonding between the azide-nitrogen and vinylic-hydrogen of molecules belonging to the adjacent stacks arranges them in a head-to-tail manner as supramolecular helices. In the crystal lattice, the azide and alkene of adjacent molecules in the supramolecular helix are suitably preorganized for their TEAC reaction. The dipeptide underwent regio- and stereospecific polymerization upon mild heating in a single-crystal-to-single-crystal fashion, yielding a triazoline-linked helical covalent polymer that could be characterized by single-crystal X-ray diffraction studies. Upon heating, the triazoline-linked polymer undergoes denitrogenation to aziridine-linked polymer, as evidenced by differential scanning calorimetry, thermogravimetric analysis, and solid-state NMR analyses.
PubMed: 35858342
DOI: 10.1073/pnas.2205320119 -
PloS One 2022For most cell culture experiments, it is indispensable that the cells are firmly anchored to culture plates, withstanding rinsing steps that can create shear forces and...
For most cell culture experiments, it is indispensable that the cells are firmly anchored to culture plates, withstanding rinsing steps that can create shear forces and tolerating temperature changes without detaching. For semi-adherent cells such as the common HEK 293 or PC-12 cells, this could so far be obtained by time-consuming plate pre-coating with cationic polymer solutions. We report here, that i) pre-coating with the cheaper poly-ethylenimine (PEI) works as well as the commonly used poly-D-lysine (PDL), but more importantly and novel ii) that simple direct addition of either PEI (1.5 μg/ml) or PDL (2 μg/ml) to the cell culture medium results in strongly anchored HEK 293 cells, indistinguishable from ones seeded on pre-coated plates. Therefore, the replacement of plate pre-coating by direct addition of either PEI or PDL gives comparable excellent results, but is highly labour-, time-, and cost-efficient. Moreover, we could show that addition of PDL or PEI also works similarly well in animal-free culture using human platelet lysate instead of fetal bovine serum. Interestingly, additional experiments showed that strong cell attachment requires only cationic polymers but not fetal bovine serum or human platelet lysate added to the medium.
Topics: Aziridines; Cell Culture Techniques; HEK293 Cells; Humans; Lysine; Polyethyleneimine; Polymers
PubMed: 35802710
DOI: 10.1371/journal.pone.0260173 -
Angewandte Chemie (Weinheim An Der... Jun 2022Herein, we present a novel approach for various asymmetric transformations of cyclic enones. The combination of readily accessible chiral diamines and sterically...
Herein, we present a novel approach for various asymmetric transformations of cyclic enones. The combination of readily accessible chiral diamines and sterically demanding flexible phosphoric acids resulted in a simple and highly tunable catalyst framework. The careful optimization of the catalyst components led to the identification of a particularly powerful and multi-purpose organocatalyst, which was successfully applied for asymmetric epoxidations, aziridinations, aza-Michael-initiated cyclizations, as well as for a novel Robinson-like Michael-initiated ring closure/aldol cyclization. High catalytic activities and excellent stereocontrol was observed for all four reaction types, indicating the excellent versatility of our catalytic system. Furthermore, a simple change in the diamine's configuration provided easy access to both product antipodes in all cases.
PubMed: 38504771
DOI: 10.1002/ange.202202189 -
ChemistryOpen Jun 2022The increasing application of positron emission tomography (PET) in nuclear medicine has stimulated the extensive development of a multitude of novel and versatile... (Review)
Review
The increasing application of positron emission tomography (PET) in nuclear medicine has stimulated the extensive development of a multitude of novel and versatile techniques to introduce fluorine-18, especially for the radiolabelling of biologically or pharmacologically active molecules. Taking into consideration that the introduction of fluorine-18 (t =109.8 min) mostly proceeds under harsh conditions, radiolabelling of such molecules represents a challenge and is of enormous interest. Ideally, it should proceed in a regioselective manner under mild physiological conditions, in an acceptable time span, with high yields and high specific activities. Special attention has been drawn to 2-fluoroethyl and 3-fluoropropyl groups, which are often the active sites of radiofluorinated compounds. Precursors containing an ammonium leaving group - such as a strained azetidinium or aziridinium moiety - can help to overcome these obstacles leading to a convenient and mild introduction of [ F]fluoride with high radiochemical yields.
Topics: Ammonium Compounds; Positron-Emission Tomography; Radiochemistry; Radiopharmaceuticals; Tomography, X-Ray Computed
PubMed: 35736542
DOI: 10.1002/open.202200039 -
Nature Communications Jun 2022The activation of aziridines typically involves the use of strong Lewis acids or transition metals, and methods relying on weak interactions are rare. Herein, we report...
The activation of aziridines typically involves the use of strong Lewis acids or transition metals, and methods relying on weak interactions are rare. Herein, we report that cooperative chalcogen bonding interactions in confined sites can activate sulfonyl-protected aziridines. Among the several possible distinct bonding modes, our experiments and computational studies suggest that an activation mode involving the cooperative Se···O and Se···N interactions is in operation. The catalytic reactions between weakly bonded supramolecular species and nonactivated alkenes are considered as unfavorable approaches. However, here we show that the activation of aziridines by cooperative Se···O and Se···N interactions enables the cycloaddition of weakly bonded aziridine-selenide complex with nonactivated alkenes in a catalytic manner. Thus, weak interactions can indeed enable these transformations and are an alternative to methods relying on strong Lewis acids.
Topics: Alkenes; Aziridines; Chalcogens; Cycloaddition Reaction; Lewis Acids
PubMed: 35732663
DOI: 10.1038/s41467-022-31293-5 -
Cancer Cell International Jun 2022Protein disulphide isomerases (PDIs) play an important role in cancer progression. However, the relative contribution of the various isoforms of PDI in tumorigenesis is...
BACKGROUND
Protein disulphide isomerases (PDIs) play an important role in cancer progression. However, the relative contribution of the various isoforms of PDI in tumorigenesis is not clear.
METHODS
The content of PDI isoforms in 22 cancer cells lines was investigated using LC-MS/MS-based proteomic analysis. The effects of PDIA1, PDIA3 and PDIA17 inhibition on the proliferation, migration and adhesion of MCF-7 and MDA-MB-231 cells, identified as high and low PDIA17 expressing cells, respectively, were assessed using novel aromatic N-sulphonamides of aziridine-2-carboxylic acid derivatives as PDI inhibitors.
RESULTS
PDIA1 and PDIA3 were the most abundant in cancer cell lysates and were also detected extracellularly in breast cancer cells (MDA-MB-231 and MCF-7). Some cancer cell lines (e.g., MCF-7, HT-29) showed upregulated expression of PDIA17, whereas in others (e.g., MDA-MB-231, 67NR), PDIA17 was not detected. The simultaneous inhibition of PDIA1 and PDIA3 showed similar anti-proliferative effects in MCF-7 and MDA-MB-231 breast cancer cells. However, the inhibition of PDIA1 and PDIA17 in the MCF-7 cell line resulted in more effective anti-adhesive and anti-proliferative effects.
CONCLUSIONS
PDIA1 and PDIA3 represent major isoforms of multiple cancer cells, and their non-selective inhibition displays significant anti-proliferative effects irrespective of whether or not PDIA17 is present. The more pronounced anti-adhesive effects of PDI inhibition in hormone-sensitive MCF-7 cells featured by higher levels of PDIs when compared to triple-negative MDA-MB-231 cells suggests that targeting extracellular PDIA1 and PDIA3 with or without additional PDIA17 inhibition may represent a strategy for personalized anti-adhesive, anti-metastatic therapy in cancers with high PDI expression.
PubMed: 35725466
DOI: 10.1186/s12935-022-02631-w -
Nature Communications Jun 2022N-functionalized aziridines, which are both useful intermediates and important synthetic targets, can be envisioned as arising from the addition of nitrenes (i.e., NR...
N-functionalized aziridines, which are both useful intermediates and important synthetic targets, can be envisioned as arising from the addition of nitrenes (i.e., NR fragments) to olefinic substrates. The exceptional reactivity of most nitrenes, in particular with respect to unimolecular decomposition, prevents general application of nitrene-transfer to the synthesis of N-functionalized aziridines. Here we demonstrate N-aryl aziridine synthesis via 1) olefin aziridination with N-aminopyridinium reagents to afford N-pyridinium aziridines followed by 2) Ni-catalyzed C-N cross-coupling of the N-pyridinium aziridines with aryl boronic acids. The N-pyridinium aziridine intermediates also participate in ring-opening chemistry with a variety of nucleophiles to afford 1,2-aminofunctionalization products. Mechanistic investigations indicate aziridine cross-coupling proceeds via a noncanonical mechanism involving initial aziridine opening promoted by the bromide counterion of the Ni catalyst, C-N cross-coupling, and finally aziridine reclosure. Together, these results provide new opportunities to achieve selective incorporation of generic aryl nitrene equivalents in organic molecules.
Topics: Alkenes; Aziridines; Boronic Acids; Catalysis; Indicators and Reagents; Stereoisomerism
PubMed: 35689000
DOI: 10.1038/s41467-022-31032-w