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Beilstein Journal of Organic Chemistry 2019Since Garner's aldehyde has several drawbacks, first of all is prone to racemization, alternative three-carbon chirons would be of great value in enantioselective... (Review)
Review
Since Garner's aldehyde has several drawbacks, first of all is prone to racemization, alternative three-carbon chirons would be of great value in enantioselective syntheses of natural compounds and/or drugs. This review article summarizes applications of -(1-phenylethyl)aziridine-2-carboxylates, -carbaldehydes and -methanols in syntheses of approved drugs and potential medications as well as of natural products mostly alkaloids but also sphingoids and ceramides and their 1- and 3-deoxy analogues and several hydroxy amino acids and their precursors. Designed strategies provided new procedures to several drugs and alternative approaches to natural products and proved efficiency of a 2-substituted -(1-phenylethyl)aziridine framework as chiron bearing a chiral auxiliary.
PubMed: 31435446
DOI: 10.3762/bjoc.15.168 -
ACS Omega May 2022Three crucial anticancer scaffolds, namely indolin-2-one, 1,3,4-thiadiazole, and aziridine, are explored to synthesize virtually screened target molecules based on the...
Three crucial anticancer scaffolds, namely indolin-2-one, 1,3,4-thiadiazole, and aziridine, are explored to synthesize virtually screened target molecules based on the c-KIT kinase protein. The stem cell factor receptor c-KIT was selected as target because most U.S. FDA-approved receptor tyrosine kinase inhibitors bearing the indolin-2-one scaffold profoundly inhibit c-KIT. Molecular hybrids of indolin-2-one with 1,3,4-thiadiazole (-) and aziridine ( and ) were afforded through a modified Schiff base green synthesis using β-cyclodextrin-SOH in water as a recyclable proton-donor catalyst. A computational study found that indolin-2,3-dione forms a supramolecular inclusion complex with β-cyclodextrin-SOH through noncovalent interactions. A molecular docking study of all the synthesized compounds was executed on the c-KIT kinase domain, and most compounds displayed binding affinities similar to that of Sunitinib. On the basis of the pharmacokinetic significance of the aryl thioether linkage in small molecules, 1,3,4-thiadiazole hybrids (-) were extended to a new series of 3-((5-(phenylthio)-1,3,4-thiadiazol-2-yl)imino)indolin-2-ones (-) via thioetherification using bis(triphenylphosphine)palladium(II)dichloride as the catalyst for C-S bond formation. Target compounds were tested against NCI-60 human cancer cell lines for a single-dose concentration. Among all three series of indolin-2-ones, the majority of compounds demonstrated broad-spectrum activity toward various cancer cell lines. Compounds and were further evaluated for a five-dose anticancer study. Compound showed a potent activity of IC = 1.47 μM against a panel of breast cancer cell lines, whereas compound exhibited the highest inhibition for a panel of colon cancer cell lines at IC = 1.40 μM. ADME property descriptors of all the target molecules are in an acceptable range. Machine learning algorithms were used to examine the metabolites and phase I and II regioselectivities of compounds and , and the results suggested that these two compounds could be potential leads for the treatment of cancer.
PubMed: 35647471
DOI: 10.1021/acsomega.2c01198 -
Organic Letters May 2024Lithiated 1,1-diborylalkanes have been used as nucleophilic coupling partners with a range of oxygen-based electrophiles, including esters, carbonyls, and epoxides....
Lithiated 1,1-diborylalkanes have been used as nucleophilic coupling partners with a range of oxygen-based electrophiles, including esters, carbonyls, and epoxides. However, their reactivity with nitrogen-based electrophiles, such as aziridines, has remained relatively understudied. Herein, we show that lithiated 1,1-diborylalkanes react with α-halo and α-tosyl aziridines to yield borylated (aminomethyl)cyclopropanes-a privileged scaffold within medicinal chemistry. The reaction displays high levels of diastereoselectivity, enabling careful control of up to three stereocenters within a single transformation. DFT studies provide insight into the reaction mechanism, which diverges from that observed with analogous epihalohydrin starting materials. Derivatization studies were also performed on the products to demonstrate the utility of the boron and amine handles.
PubMed: 38669565
DOI: 10.1021/acs.orglett.4c00987 -
Angewandte Chemie (International Ed. in... Jul 2021Aziridine is a characteristically reactive molecule with increased bioactivity due to its strained ring structure. Here, we investigated the biosynthesis of...
Aziridine is a characteristically reactive molecule with increased bioactivity due to its strained ring structure. Here, we investigated the biosynthesis of 2-aminoisobutyric acid (AIB) in Penicillium, and successfully reconstituted the three-step biosynthesis from L-Val to AIB in vitro. This previously unknown aziridine formation pathway proceeded with the non-heme iron and α-ketoglutarate-dependent (Fe /αKG) oxygenase TqaL, followed by aziridine ring opening by the haloalkanoic acid dehalogenase (HAD)-type hydrolase TqaF, and subsequent oxidative decarboxylation by the NovR/CloR-like non-heme iron oxygenase TqaM. Furthermore, the X-ray crystal structure of the C-N bond forming Fe /αKG oxygenase TqaL was solved at 2.0 Å resolution. This work presents the first molecular basis for aziridine biogenesis, thereby expanding the catalytic repertoire of the Fe /αKG oxygenases. We also report the unique aziridine ring opening by a HAD-type hydrolase and the remarkable oxidative decarboxylation by a non-heme iron oxygenase to produce AIB.
Topics: Aminoisobutyric Acids; Aziridines; Fungi; Iron; Ketoglutaric Acids; Kinetics; Oxidation-Reduction; Oxygenases
PubMed: 33973699
DOI: 10.1002/anie.202104644 -
The Journal of Organic Chemistry Mar 2022The first direct general method for Me aziridination of electron-deficient olefins, enones, is described using -methyl--tosylhydroxylamine as the aminating agent in the...
The first direct general method for Me aziridination of electron-deficient olefins, enones, is described using -methyl--tosylhydroxylamine as the aminating agent in the presence of a Cu(OTf) catalyst. The aziridination of vinyl ketones, hitherto unknown for -Me as well as -H, has been achieved efficiently. The open-flask reaction is stereospecific, operationally simple, and additive-free. It also efficiently affords -H aziridinated products under a similar reaction condition.
Topics: Alkenes; Aziridines; Catalysis; Ketones; Molecular Structure
PubMed: 35171590
DOI: 10.1021/acs.joc.1c02785 -
ChemistryOpen Jun 2024In previous works, we demonstrated that tertiary 3-chloropiperidines are potent chemotherapeutics, alkylating the DNA through the formation of bicyclic aziridinium ions....
In previous works, we demonstrated that tertiary 3-chloropiperidines are potent chemotherapeutics, alkylating the DNA through the formation of bicyclic aziridinium ions. Herein, we report the synthesis of novel secondary 3-chloropiperidine analogues. The synthesis incorporates a new procedure to monochlorinate unsaturated primary amines utilizing N-chlorosuccinimide, while carefully monitoring the temperature to prevent dichlorination. Furthermore, we successfully isolated highly strained bicyclic aziridines by treating the secondary 3-chloropiperidines with a sufficient amount of base. We conclude this work with a DNA cleavage assay as a proof of principle, comparing our previously known substrates to the novel compounds. In this, the secondary 3-chloropiperidine as well as the isolated bicyclic aziridine, proved to be more effective than their tertiary counterpart.
Topics: Piperidines; Antineoplastic Agents, Alkylating; Alkylating Agents; DNA Cleavage; Humans; Aziridines; DNA; Succinimides
PubMed: 38088585
DOI: 10.1002/open.202300181 -
Cellular Physiology and Biochemistry :... Sep 2022The development of new nanomaterials has been growing in recent decades to bring benefits in several areas, especially carbon-based nanoparticles, which have unique...
BACKGROUND/AIMS
The development of new nanomaterials has been growing in recent decades to bring benefits in several areas, especially carbon-based nanoparticles, which have unique physical-chemical properties and allow to take on several applications. Consequently, the use of new nanomaterials without previous toxicological studies raises concern about possible harmful health effects. The aim of this study was to investigate the cytotoxic profile of a new multi-walled carbon nanotube (MWCNT) functionalized with tetraethylenepentamine called OCNT-TEPA using in vitro assays in murine macrophage cells linage J774 A.1.
METHODS
OCNT-TEPA was characterized by transmission electron microscopy (TEM) and high resolution TEM (HR-TEM), scanning electron microscopy (SEM), zeta potential and dynamic light scattering (DLS), and its cytotoxic effects were evaluated at 24 and 48 hours by cell viability assays (MTT and NR), morphology and cell recovery (optic microscopy and clonogenic assay), formation of reactive oxygen (ROS) and nitric oxide (NO) species, inflammatory profile (IL-6 and TNF cytokines), mitochondrial membrane potential analysis (MMP), activation of the caspase 3 pathway and cell death (flow cytometry).
RESULTS
The data showed a significant decrease in cell viability, increased production of ROS and NO, alteration of mitochondrial membrane potential, increased levels of inflammatory cytokines, alteration of cell morphology, activation of the Caspase 3 pathway and consequently cell death, in the highest concentrations of OCNT-TEPA tested in the periods of 24 and 48 hours.
CONCLUSION
The analyses showed that OCNT-TEPA has a dose-dependent cytotoxic profile, which may be harmful to murine macrophages (J774 A.1) and may represent a health risk.
Topics: Animals; Antineoplastic Agents; Caspase 3; Cell Survival; Cytokines; Interleukin-6; Macrophages; Mice; Nanotubes, Carbon; Nitric Oxide; Oxygen; Reactive Oxygen Species; Triethylenephosphoramide
PubMed: 36168820
DOI: 10.33594/000000573 -
Clinical Pharmacology and Therapeutics Jan 2024A toxicity-reduced conditioning regimen with treosulfan, fludarabine, and thiotepa in patients with high-risk β-thalassemia major has significantly improved...
A toxicity-reduced conditioning regimen with treosulfan, fludarabine, and thiotepa in patients with high-risk β-thalassemia major has significantly improved hematopoietic stem cell transplantation (HCT) outcomes. However, complications resulting from regimen-related toxicities (RRTs), mixed chimerism, and graft rejection remain a challenge. We evaluated the dose-exposure-response relationship of treosulfan and its active metabolite S, S-EBDM, in a uniform cohort of patients with β-thalassemia major to identify whether therapeutic drug monitoring (TDM) and dose adjustment of treosulfan is feasible. Plasma treosulfan/S, S-EBDM levels were measured in 77 patients using a validated liquid chromatography with tandem mass spectrometry method, and the pharmacokinetic parameters were estimated using nlmixr2. The influence of treosulfan and S, S-EBDM exposure, and GSTA1/NQO1 polymorphisms on graft rejection, RRTs, chimerism status, and 1-year overall survival (OS), and thalassemia-free survival (TFS) were assessed. We observed that treosulfan exposure was lower in patients with graft rejection than those without (1,655 vs. 2,037 mg•h/L, P = 0.07). Pharmacodynamic modeling analysis to identify therapeutic cutoff revealed that treosulfan exposure ≥1,660 mg•hour/L was significantly associated with better 1-year TFS (97% vs. 81%, P = 0.02) and a trend to better 1-year OS (90% vs. 69%, P = 0.07). Further, multivariate analysis adjusting for known pre-HCT risk factors also revealed treosulfan exposure <1,660 mg•h/L (hazard ratio (HR) = 3.23; 95% confidence interval (CI) = 1.12-9.34; P = 0.03) and GSTA1*B variant genotype (HR = 3.75; 95% CI = 1.04-13.47; P = 0.04) to be independent predictors for inferior 1-year TFS. We conclude that lower treosulfan exposure increases the risk of graft rejection and early transplant-related mortality affecting TFS. As no RRTs were observed with increasing treosulfan exposure, TDM-based dose adjustment could be feasible and beneficial.
Topics: Humans; beta-Thalassemia; Busulfan; Hematopoietic Stem Cell Transplantation; Thiotepa; Transplantation Conditioning; Graft vs Host Disease
PubMed: 37846495
DOI: 10.1002/cpt.3078 -
Molecules (Basel, Switzerland) Oct 2022Multi-substituted pyrroles are synthesized from regiospecific aziridine ring-opening and subsequent intramolecular cyclization with a carbonyl group at the -position in...
Multi-substituted pyrroles are synthesized from regiospecific aziridine ring-opening and subsequent intramolecular cyclization with a carbonyl group at the -position in the presence of Lewis acid or protic acid. This method is highly atom economical where all the atoms of the reactants are incorporated into the final product with the removal of water. This new protocol is applied to the synthesis of various pyrroles, including natural products.
Topics: Pyrroles; Lewis Acids; Aziridines; Biological Products; Water
PubMed: 36296466
DOI: 10.3390/molecules27206869 -
Organic & Biomolecular Chemistry Jan 2021A one-pot aziridine opening reaction by glycosyl thiols generated in situ from the corresponding anomeric thio-acetates affords thio-glycosides with a...
A one-pot aziridine opening reaction by glycosyl thiols generated in situ from the corresponding anomeric thio-acetates affords thio-glycosides with a pseudo-disaccharide structure and an N-linked tether. The scope of the one-pot aziridine opening reaction was explored on a series of mono- and disaccharides, creating a class of pseudo-glycosidic compounds with potential for further functionalization. Unexpected anomerization of glycosyl thiols was observed under the reaction conditions and the influence of temperature, base and solvent on the isomerization was investigated. Single isomers were obtained in good to acceptable yields for mannose, rhamnose and sialic acid derivatives. The class of thio-glycomimetics synthesized can potentially be recognized by various lectins, while presenting hydrolytic and enzymatic stability. The nitrogen functionality incorporated in the glycomimetics can be exploited for further functionalization, including tethering to linkers, scaffolds or peptide residues.
PubMed: 33283815
DOI: 10.1039/d0ob01956a