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Molecules (Basel, Switzerland) Jul 2020Superelectrophiles are reactive species that often carry multiple positive charges. They have been useful in numerous synthetic methods and they often exhibit highly... (Review)
Review
Superelectrophiles are reactive species that often carry multiple positive charges. They have been useful in numerous synthetic methods and they often exhibit highly unusual reactivities. Recent advances in superelectrophile chemistry are discussed in this review.
Topics: Aza Compounds; Cyclization; Electrochemistry; Mesylates; Quinolones
PubMed: 32707680
DOI: 10.3390/molecules25143281 -
Journal of Pharmacological Sciences Sep 2023Premature ovarian insufficiency (POI) is a clinical syndrome that declines ovarian function in women. Berberine (BBR) is a compound with anti-inflammatory, antioxidant,...
Premature ovarian insufficiency (POI) is a clinical syndrome that declines ovarian function in women. Berberine (BBR) is a compound with anti-inflammatory, antioxidant, and anti-apoptotic activities. However, the role of BBR on POI is still unknown. In this study, we investigated the role of BBR on ovarian function decline by establishing a POI mouse model using cyclophosphamide (CTX) and busulfan (BU). Our results showed that POI was attenuated by BBR, which was evidenced by enhanced body weight and ovarian weight, improved morphology of ovary, increased the number of healthy follicles, decreased the production of atretic follicles and restored serum hormone levels, including estradiol, anti-Müllerian hormone and follicle-stimulating hormone. In addition, we showed that germ cell function markers, mouse vasa homologue (MVH) and octamer-binding transcription factor 4 (OCT4) were enhanced by BBR, at both protein and mRNA levels. Furthermore, our results revealed that BBR inhibited inflammation and oxidative stress by reducing nuclear factor kappa B (NF-κB) and enhancing nuclear factor erythroid 2-related factor 2 (Nrf2) pathways. Taken together, we demonstrate that BBR can effectively improve ovarian function in POI mice, which is mainly mediated by reducing oxidative stress and inflammatory response. Our study also provides new strategy for POI treatment.
Topics: Mice; Female; Humans; Animals; Busulfan; Berberine; Primary Ovarian Insufficiency; Cyclophosphamide; Estradiol
PubMed: 37524454
DOI: 10.1016/j.jphs.2023.07.004 -
IUCrData Sep 2020In the title complex, [Zn(CFOS)Cl(CHClN)]·CHCN, the zinc(II) core is fivefold coordinated by one chloride, one tri-fluoro-methane-sulfonate O atom and three terpyridine...
In the title complex, [Zn(CFOS)Cl(CHClN)]·CHCN, the zinc(II) core is fivefold coordinated by one chloride, one tri-fluoro-methane-sulfonate O atom and three terpyridine N atoms in a slightly distorted square-pyramidal geometry. The structure provides a distinct example amongst other zinc(II) 4-chloro-terpyridine complexes because of the unusual planarity of the coordinated chloride, the short length of the Zn-N bond opposite to the chloride ligand [1.9572 (15) Å], and the presence of an elongated Zn-O bond [2.3911 (14) Å] in the coordinated tri-fluoro-methane-sulfonate ion. A molecule of acetonitrile is also found in the asymmetric unit of the title complex.
PubMed: 36338906
DOI: 10.1107/S2414314620012924 -
Plants (Basel, Switzerland) Oct 2022synthesizes bioactive therapeutic metabolites, known as monoterpenoid indole alkaloids (MIAs), including antineoplastic vinblastine and vincristine, which have high...
Ethyl Methane Sulfonate and Sodium Azide-Mediated Chemical and X-ray-Mediated Physical Mutagenesis Positively Regulate Gene Activity and Biosynthesis of Antineoplastic Vinblastine in .
synthesizes bioactive therapeutic metabolites, known as monoterpenoid indole alkaloids (MIAs), including antineoplastic vinblastine and vincristine, which have high global demand, and antihypertensive ajmalicine, a serpentine. However, the in planta biosynthesis and accumulation of these phytopharmaceuticals are very low, attributed to their high cytotoxicity in the plant. Considering the low in planta concentration and over-harvesting of plant resources, biotechnological interventions have been undertaken to enhance the production of MIAs in plant systems. The present study was carried out to mutation through chemical and physical mutagenesis with sodium azide, ethyl methane sulfonate and X-rays, respectively, on to determine their possible effects on the transcriptional modulation of MIA biosynthetic pathways in planta. The chemical mutagenesis resulted in delayed seed pod development in mutated plants, with distinct leaf morphology and flower color. However, X-ray mutagenesis resulted in pollen-less sterile flowers. An HPLC analysis confirmed the higher catharanthine, vindoline and vinblastine content in sodium azide and X-ray mutants, and was further supported by higher transcript levels estimated through real-time PCR analysis. The transcription factors and were found negatively regulated along with major MIA pathway genes in chemical mutants and their M generation, but showed positive regulation in X-ray M mutants. The induced mutagenesis of provides a prospective strategy to modulate plant transcriptomes and enhance the biosynthesis of pharmaceutically important antineoplastic vinblastine in the plant.
PubMed: 36365340
DOI: 10.3390/plants11212885 -
IUCrData Oct 2021The central Ag atom of the title salt, [Ag(INAM)](CFSO)·2CHCN, where INAM is isonicotinamide (CHNO), is twofold coordinated by the pyridine N atoms of two...
The central Ag atom of the title salt, [Ag(INAM)](CFSO)·2CHCN, where INAM is isonicotinamide (CHNO), is twofold coordinated by the pyridine N atoms of two isonicotinamide ligands creating a slightly distorted linear mol-ecular geometry. The formation of polymeric chains {[Ag(INAM)]} , held together by discrete hydrogen bonds through the amide group of the INAM ligand leaves voids for non-coordinating aceto-nitrile mol-ecules that inter-act the silver metal center regium bonds.
PubMed: 36340985
DOI: 10.1107/S2414314621010737 -
Acta Crystallographica. Section E,... May 2024The synthesis, crystallization and characterization of a tri-fluoro-methane-sulfonate salt of 5,10,15,20-tetra-kis-(1-benzyl-pyridin-1-ium-4-yl)-21,23-por-phy-rin, CHN...
The synthesis, crystallization and characterization of a tri-fluoro-methane-sulfonate salt of 5,10,15,20-tetra-kis-(1-benzyl-pyridin-1-ium-4-yl)-21,23-por-phy-rin, CHN ·4CFSO ·4HO, ·OTf, are reported in this work. The reaction between 5,10,15,20-tetra-kis-(pyridin-4-yl)-21,23-porphyrin and benzyl bromide in the presence of 0.1 equiv. of Ca(OH) in CHCN under reflux with an N atmosphere and subsequent treatment with silver tri-fluoro-methane-sulfonate (AgOTf) salt produced a red-brown solution. This reaction mixture was filtered and the solvent was allowed to evaporate at room temperature for 3 d to give ·OTf. Crystal structure determination by single-crystal X-ray diffraction (SCXD) revealed that ·OTf crystallizes in the space group 2/. The asymmetric unit contains half a porphyrin mol-ecule, two tri-fluoro-methane-sulfonate anions and two water mol-ecules of crystallization. The macrocycle of tetra-pyrrole moieties is planar and unexpectedly it has coordinated Ca ions in occupational disorder. This Ca ion has only 10% occupancy (CHCaFNOS). The pyridinium rings bonded to methyl-ene groups from porphyrin are located in two different arrangements in almost orthogonal positions between the plane formed by the porphyrin and the pyridinium rings. The crystal structure features cation⋯π inter-actions between the Ca atom and the π-system of the phenyl ring of neighboring mol-ecules. Both tri-fluoro-methane-sulfonate anions are found at the periphery of , forming hydrogen bonds with water mol-ecules.
PubMed: 38845702
DOI: 10.1107/S205698902400447X -
Science (New York, N.Y.) Nov 2021To date, it remains challenging to selectively migrate a carbonyl oxygen within a given molecular scaffold, especially to an adjacent carbon. In this work, we describe a...
To date, it remains challenging to selectively migrate a carbonyl oxygen within a given molecular scaffold, especially to an adjacent carbon. In this work, we describe a simple one- or two-pot protocol that transposes a ketone to the vicinal carbon. This approach first converts the ketone to the corresponding alkenyl triflate, which can then undergo the palladium- and norbornene-catalyzed regioselective α-amination and ipso-hydrogenation enabled by a bifunctional hydrogen and nitrogen donor. The resulting “transposed enamine” intermediate can subsequently be hydrolyzed to produce the 1,2-carbonyl–migrated product. This method allows rapid access to unusual bioactive analogs through late-stage functionalization.
Topics: Amination; Carbon; Catalysis; Chemistry, Pharmaceutical; Hydrogen; Hydrogenation; Ketones; Mesylates; Molecular Structure; Norbornanes; Oxygen; Palladium; Technology, Pharmaceutical
PubMed: 34735246
DOI: 10.1126/science.abl7854 -
Haematologica Jul 2023Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment for myelofibrosis. However, the optimal conditioning regimen either with...
Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment for myelofibrosis. However, the optimal conditioning regimen either with reduced-intensity conditioning (RIC) or myeloablative conditioning (MAC) is not well known. Using the Center for International Blood and Marrow Transplant Research database, we identified adults aged ≥18 years with myelofibrosis undergoing allo-HCT between 2008-2019 and analyzed the outcomes separately in the RIC and MAC cohorts based on the conditioning regimens used. Among 872 eligible patients, 493 underwent allo-HCT using RIC (fludarabine/ busulfan n=166, fludarabine/melphalan n=327) and 379 using MAC (fludarabine/busulfan n=247, busulfan/cyclophosphamide n=132). In multivariable analysis with RIC, fludarabine/melphalan was associated with inferior overall survival (hazard ratio [HR]=1.80; 95% confidenec interval [CI]: 1.15-2.81; P=0.009), higher early non-relapse mortality (HR=1.81; 95% CI: 1.12-2.91; P=0.01) and higher acute graft-versus-host disease (GvHD) (grade 2-4 HR=1.45; 95% CI: 1.03-2.03; P=0.03; grade 3-4 HR=2.21; 95%CI: 1.28-3.83; P=0.004) compared to fludarabine/busulfan. In the MAC setting, busulfan/cyclophosphamide was associated with a higher acute GvHD (grade 2-4 HR=2.33; 95% CI: 1.67-3.25; P<0.001; grade 3-4 HR=2.31; 95% CI: 1.52-3.52; P<0.001) and inferior GvHD-free relapse-free survival (GRFS) (HR=1.94; 95% CI: 1.49-2.53; P<0.001) as compared to fludarabine/busulfan. Hence, our study suggests that fludarabine/busulfan is associated with better outcomes in RIC (better overall survival, lower early non-relapse mortality, lower acute GvHD) and MAC (lower acute GvHD and better GRFS) in myelofibrosis.
Topics: Adult; Humans; Adolescent; Primary Myelofibrosis; Busulfan; Melphalan; Retrospective Studies; Hematopoietic Stem Cell Transplantation; Cyclophosphamide; Graft vs Host Disease; Transplantation Conditioning; Vidarabine
PubMed: 36779595
DOI: 10.3324/haematol.2022.281958 -
The Journal of Allergy and Clinical... Mar 2022Allogeneic hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis (HLH) disorders is associated with substantial morbidity and mortality.
BACKGROUND
Allogeneic hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis (HLH) disorders is associated with substantial morbidity and mortality.
OBJECTIVE
The effect of conditioning regimen groups of varying intensity on outcomes after transplantation was examined to identify an optimal regimen or regimens for HLH disorders.
METHODS
We studied 261 patients with HLH disorders transplanted between 2005 and 2018. Risk factors for transplantation outcomes by conditioning regimen groups were studied by Cox regression models.
RESULTS
Four regimen groups were studied: (1) fludarabine (Flu) and melphalan (Mel) in 123 subjects; (2) Flu, Mel, and thiotepa (TT) in 28 subjects; (3) Flu and busulfan (Bu) in 14 subjects; and (4) Bu and cyclophosphamide (Cy) in 96 subjects. The day 100 incidence of veno-occlusive disease was lower with Flu/Mel (4%) and Flu/Mel/TT (0%) compared to Flu/Bu (14%) and Bu/Cy (22%) (P < .001). The 6-month incidence of viral infections was highest after Flu/Mel (72%) and Flu/Mel/TT (64%) compared to Flu/Bu (39%) and Bu/Cy (38%) (P < .001). Five-year event-free survival (alive and engrafted without additional cell product administration) was lower with Flu/Mel (44%) compared to Flu/Mel/TT (70%), Flu/Bu (79%), and Bu/Cy (61%) (P = .002). The corresponding 5-year overall survival values were 68%, 75%, 86%, and 64%, and did not differ by conditioning regimen (P = .19). Low event-free survival with Flu/Mel is attributed to high graft failure (42%) compared to Flu/Mel/TT (15%), Flu/Bu (7%), and Bu/Cy (18%) (P < .001).
CONCLUSIONS
Given the high rate of graft failure with Flu/Mel and the high rate of veno-occlusive disease with Bu/Cy and Flu/Bu, Flu/Mel/TT may be preferred for HLH disorders. Prospective studies are warranted.
Topics: Busulfan; Cyclophosphamide; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Lymphohistiocytosis, Hemophagocytic; Melphalan; Thiotepa; Transplantation Conditioning; Vidarabine
PubMed: 34375618
DOI: 10.1016/j.jaci.2021.07.031 -
ELife Jun 2023The replication checkpoint is essential for accurate DNA replication and repair, and maintenance of genomic integrity when a cell is challenged with genotoxic stress....
The replication checkpoint is essential for accurate DNA replication and repair, and maintenance of genomic integrity when a cell is challenged with genotoxic stress. Several studies have defined the complement of proteins that change subcellular location in the budding yeast following chemically induced DNA replication stress using methyl methanesulfonate (MMS) or hydroxyurea (HU). How these protein movements are regulated remains largely unexplored. We find that the essential checkpoint kinases Mec1 and Rad53 are responsible for regulating the subcellular localization of 159 proteins during MMS-induced replication stress. Unexpectedly, Rad53 regulation of the localization of 52 proteins is independent of its known kinase activator Mec1, and in some scenarios independent of Tel1 or the mediator proteins Rad9 and Mrc1. We demonstrate that Rad53 is phosphorylated and active following MMS exposure in cells lacking Mec1 and Tel1. This noncanonical mode of Rad53 activation depends partly on the retrograde signaling transcription factor Rtg3, which also facilitates proper DNA replication dynamics. We conclude that there are biologically important modes of Rad53 protein kinase activation that respond to replication stress and operate in parallel to Mec1 and Tel1.
Topics: Protein Serine-Threonine Kinases; Cell Cycle Proteins; Saccharomyces cerevisiae Proteins; Intracellular Signaling Peptides and Proteins; Checkpoint Kinase 2; Saccharomyces cerevisiae; Phosphorylation; DNA Damage; Methyl Methanesulfonate; DNA Replication
PubMed: 37278514
DOI: 10.7554/eLife.82483