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Journal of the American Chemical Society Apr 2024The C(sp)-H bond oxygenation of a variety of cyclopropane containing hydrocarbons with hydrogen peroxide catalyzed by manganese complexes containing aminopyridine...
The C(sp)-H bond oxygenation of a variety of cyclopropane containing hydrocarbons with hydrogen peroxide catalyzed by manganese complexes containing aminopyridine tetradentate ligands was carried out. Oxidations were performed in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) and 2,2,2-trifluoroethanol (TFE) using different manganese catalysts and carboxylic acid co-ligands, where steric and electronic properties were systematically modified. Functionalization selectively occurs at the most activated C-H bonds that are α- to cyclopropane, providing access to carboxylate or 2,2,2-trifluoroethanolate transfer products, with no competition, in favorable cases, from the generally dominant hydroxylation reaction. The formation of mixtures of unrearranged and rearranged esters (oxidation in HFIP in the presence of a carboxylic acid) and ethers (oxidation in TFE) with full control over diastereoselectivity was observed, confirming the involvement of delocalized cationic intermediates in these transformations. Despite such a complex mechanistic scenario, by fine-tuning of catalyst and carboxylic acid sterics and electronics and leveraging on the relative contribution of cationic pathways to the reaction mechanism, control over product chemoselectivity could be systematically achieved. Taken together, the results reported herein provide powerful catalytic tools to rationally manipulate ligand transfer pathways in C-H oxidations of cyclopropane containing hydrocarbons, delivering novel products in good yields and, in some cases, outstanding selectivities, expanding the available toolbox for the development of synthetically useful C-H functionalization procedures.
PubMed: 38506665
DOI: 10.1021/jacs.3c11555 -
Plants (Basel, Switzerland) Feb 20243-demethyl-2-geranyl-4-prenylbellidifoline (DGP), a natural xanthone isolated from , has previously demonstrated remarkable diuretic and renal protective actions. The...
3-demethyl-2-geranyl-4-prenylbellidifoline (DGP), a natural xanthone isolated from , has previously demonstrated remarkable diuretic and renal protective actions. The present study expands its actions on the cardiovascular system by evaluating its vasorelaxant and blood pressure-lowering effects in spontaneously hypertensive rats (SHRs). Aortic endothelium-intact (E+) preparations of SHRs pre-contracted by phenylephrine and exposed to cumulative concentrations of extract, fractions, and DGP exhibited a significant relaxation compared to vehicle-only exposed rings. The non-selective muscarinic receptor antagonist (atropine), the non-selective inhibitor of nitric oxide synthase (L-NAME), as well as the inhibitor of soluble guanylate cyclase (ODQ) altogether avoided DGP-induced relaxation. Tetraethylammonium (small conductance Ca-activated K channel blocker), 4-aminopyridine (a voltage-dependent K channel blocker), and barium chloride (an influx-rectifying K channel blocker) significantly reduced DGP capacity to induce relaxation without the interference of glibenclamide (an ATP-sensitive inward rectifier 6.1 and 6.2 K channel blocker). Additionally, administration of DGP, 1 mg/kg i.v., decreased the mean, systolic, and diastolic arterial pressures, and the heart rate of SHRs. The natural xanthone DGP showed promising potential as an endothelium-dependent vasorelaxant, operating through the nitric oxide pathway and potassium channels, ultimately significantly reducing blood pressure in hypertensive rats.
PubMed: 38498544
DOI: 10.3390/plants13040528 -
EBioMedicine Apr 2024In male mice, a circadian rhythm in myogenic reactivity influences the extent of brain injury following subarachnoid haemorrhage (SAH). We hypothesized that female mice...
BACKGROUND
In male mice, a circadian rhythm in myogenic reactivity influences the extent of brain injury following subarachnoid haemorrhage (SAH). We hypothesized that female mice have a different cerebrovascular phenotype and consequently, a distinct SAH-induced injury phenotype.
METHODS
SAH was modelled by pre-chiasmatic blood injection. Olfactory cerebral resistance arteries were functionally assessed by pressure myography; these functional assessments were related to brain histology and neurobehavioral assessments. Cystic fibrosis transmembrane conductance regulator (CFTR) expression was assessed by PCR and Western blot. We compared non-ovariectomized and ovariectomized mice.
FINDINGS
Cerebrovascular myogenic reactivity is not rhythmic in females and no diurnal differences in SAH-induced injury are observed; ovariectomy does not unmask a rhythmic phenotype for any endpoint. CFTR expression is rhythmic, with similar expression levels compared to male mice. CFTR inhibition studies, however, indicate that CFTR activity is lower in female arteries. Pharmacologically increasing CFTR expression in vivo (3 mg/kg lumacaftor for 2 days) reduces myogenic tone at Zeitgeber time 11, but not Zeitgeber time 23. Myogenic tone is not markedly augmented following SAH in female mice and lumacaftor loses its ability to reduce myogenic tone; nevertheless, lumacaftor confers at least some injury benefit in females with SAH.
INTERPRETATION
Female mice possess a distinct cerebrovascular phenotype compared to males, putatively due to functional differences in CFTR regulation. This sex difference eliminates the CFTR-dependent cerebrovascular effects of SAH and may alter the therapeutic efficacy of lumacaftor compared to males.
FUNDING
Brain Aneurysm Foundation, Heart and Stroke Foundation and Ted Rogers Centre for Heart Research.
Topics: Male; Mice; Female; Animals; Cystic Fibrosis Transmembrane Conductance Regulator; Subarachnoid Hemorrhage; Sex Characteristics; Aminopyridines; Benzodioxoles
PubMed: 38490104
DOI: 10.1016/j.ebiom.2024.105058 -
Minerva Gastroenterology Jun 2024
Topics: Humans; Breast Neoplasms; Probiotics; Benzimidazoles; Dietary Supplements; Female; Diarrhea; Aminopyridines
PubMed: 38483445
DOI: 10.23736/S2724-5985.24.03647-7 -
Pharmacology Research & Perspectives Apr 2024Considering the importance of pain and stress, we decided to investigate the intra-anterior cingulate cortex (ACC) microinjection of histamine and mepyramine alone and...
Considering the importance of pain and stress, we decided to investigate the intra-anterior cingulate cortex (ACC) microinjection of histamine and mepyramine alone and concurrently on acute pain induced by hot plate following restraint stress in male rats. 24-gauge, 10 mm stainless steel guide cannula was implanted over the ACC in the incised scalp of 4 groups. Restraint stress in healthy rats produced a significant increase (p < .05) in the pain threshold. The simultaneous microinjection of 4 μg/side histamine and 8 μg/side mepyramine as a histaminergic system inverse agonist in healthy nonrestraint animals did not affect the pain threshold. Although Histamine decreased the threshold of pain meaningfully, mepyramine elevated it in a significant manner (p < .05). In the restrained animals, intra-ACC microinjection of histamine produced no significant impact on the pain threshold. However, intra-ACC microinjection of mepyramine before histamine, significantly (p < .01) altered the result and enhanced the threshold of pain. The results of our study demonstrated that histaminergic neurons have an important role in the processing of pain in the ACC following restraint stress.
Topics: Rats; Male; Animals; Histamine; Receptors, Histamine H1; Gyrus Cinguli; Pyrilamine; Nociception; Drug Inverse Agonism; Pain
PubMed: 38483045
DOI: 10.1002/prp2.1188 -
International Journal of Chronic... 2024The clinical efficacy of roflumilast, an oral phosphodiesterase-4 inhibitor, has been demonstrated in patients with severe chronic obstructive pulmonary disease (COPD).... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The clinical efficacy of roflumilast, an oral phosphodiesterase-4 inhibitor, has been demonstrated in patients with severe chronic obstructive pulmonary disease (COPD). However, roflumilast has shown frequent adverse drug reactions (ADRs). This study was performed to investigate the dosing strategy that will improve adherence to roflumilast in COPD.
METHODS
We conducted a systematic review and meta-analysis using PubMed, Embase, and Cochrane Central Register. The dosing strategy for roflumilast was classified into a dose-escalation group and a low-dose group. We investigated clinical outcomes according to dosing strategy.
RESULTS
Five clinical trials involving 2424 patients were included. Both the dose-escalation and the low-dose groups showed a decrease in discontinuation rate compared to the standard dosing group for roflumilast (risk ratio [RR], 0.81; 95% confidence interval [CI], 0.67-0.97; = 0.02 and RR, 0.62; 95% CI, 0.48-0.80; < 0.01, respectively). In the two strategies, the pooled proportions of discontinuation were 27.9% and 11.7%, respectively. Although the pooled proportion of any ADR was not statistically decreased in the two strategies, diarrhea was significantly reduced in the low-dose group compared to the standard group (RR, 0.58; 95% CI, 0.42-0.82; < 0.01). The pooled incidence of acute exacerbations was similar between the low-dose and the standard groups (22.9% and 20.1%, respectively; = 0.27).
CONCLUSION
Our findings show that the two alternative dosing strategies might have the benefit of improving adherence to roflumilast in COPD. Further large-scale trials are required to support our findings.
Topics: Humans; Pulmonary Disease, Chronic Obstructive; Aminopyridines; Benzamides; Cyclopropanes; Phosphodiesterase 4 Inhibitors
PubMed: 38476122
DOI: 10.2147/COPD.S440252 -
International Journal of Molecular... Feb 2024p.Asn1303Lys (N1303K) is a common missense variant of the gene, causing cystic fibrosis (CF). In this study, we initially evaluated the influence of modulators on the...
p.Asn1303Lys (N1303K) is a common missense variant of the gene, causing cystic fibrosis (CF). In this study, we initially evaluated the influence of modulators on the restoration of N1303K- function using intestinal organoids derived from four CF patients expressing the N1303K variant. The forskolin-induced swelling assay in organoids offered valuable insights about the beneficial effects of VX-770 + VX-661 + VX-445 (Elexacaftor + Tezacaftor + Ivacaftor, ETI) on N1303K- function restoration and about discouraging the prescription of VX-770 + VX-809 (Ivacaftor + Lumacaftor) or VX-770 + VX-661 (Ivacaftor + Tezacaftor) therapy for N1303K/class I patients. Then, a comprehensive assessment was conducted on an example of one patient with the N1303K/class I genotype to examine the ETI effect on the restoration of N1303K- function using in vitro the patient's intestinal organoids, ex vivo the intestinal current measurements (ICM) method and assessment of the clinical status before and after targeted therapy. All obtained results are consistent with each other and have proven the effectiveness of ETI for the N1303K variant. ETI produced a significant positive effect on forskolin-induced swelling in N1303K/class I organoids indicating functional improvement of the protein; ICM demonstrated that ETI therapy restored function in the intestinal epithelium after three months of treatment, and the patient improved his clinical status and lung function, increased his body mass index (BMI) and reduced the lung pathogenic flora diversity, surprisingly without improving the sweat test results.
Topics: Humans; Cystic Fibrosis Transmembrane Conductance Regulator; Colforsin; Mutation; Cystic Fibrosis; Benzodioxoles; Aminophenols; Aminopyridines; Quinolones
PubMed: 38474016
DOI: 10.3390/ijms25052770 -
Archives of Gynecology and Obstetrics Jun 2024Following the positive iDFS and OS results of the phase III clinical trials monarchE, NATALEE and OlympiA, new oral anticancer agents (the CDK4/6 inhibitors abemaciclib,...
BACKGROUND
Following the positive iDFS and OS results of the phase III clinical trials monarchE, NATALEE and OlympiA, new oral anticancer agents (the CDK4/6 inhibitors abemaciclib, ribociclib as well as the PARP inhibitor olaparib) have recently been introduced into the treatment of high-risk early breast cancer (eBC). However, only few male patients were included in these trials (0.4%, 0.6% and 0.3%, respectively). The objective of this real-world analysis was to determine the proportion of male patients with eBC fulfilling the clinical high-risk criteria of above-mentioned trials.
PATIENTS AND METHODS
We conducted a data inquiry and analysis with the Cancer Registry of Baden-Württemberg of men with breast cancer diagnosed between January 1, 2015 and December 31, 2021. Men with eBC were identified and the number of patients at clinical high-risk according to the inclusion criteria of monarchE, NATALEE and OlympiA was assessed.
RESULTS
Of 397 men with eBC, 354 (89.1%) had a HR + /Her2- and 4 (1.0%) a triple-negative subtype. 84 patients (21.2%) met the clinical high-risk criteria according to the monarchE, 189 (47.6%) those according to the NATALEE and 50 (12.6%) those according to the OlympiA trial.
CONCLUSION
In a large real-world sample, more men with eBC are at clinical high risk according to the inclusion criteria of monarchE, NATALEE and OlympiA than would be expected in women. This is most likely due to more advanced stages at initial diagnosis in men. To evaluate whether CDK4/6 and PARP inhibitors improve prognosis also in men should be the topic of future real- world analyses.
Topics: Humans; Male; Breast Neoplasms, Male; Registries; Middle Aged; Aged; Feasibility Studies; Chemotherapy, Adjuvant; Adult; Molecular Targeted Therapy; Aminopyridines; Poly(ADP-ribose) Polymerase Inhibitors; Benzimidazoles; Aged, 80 and over; Antineoplastic Agents; Purines
PubMed: 38472501
DOI: 10.1007/s00404-024-07405-5 -
Cancer Medicine Feb 2024Chidamide is a selective histone deacetylase inhibitor approved for patients with hormone receptor (HoR)-positive and HER2-negative metastatic breast cancer (MBC). We...
Treatment patterns and clinical outcomes of chidamide combined with endocrine therapy in hormone receptor-positive, HER2-negative metastatic breast cancer: A real-world multicenter study.
BACKGROUND
Chidamide is a selective histone deacetylase inhibitor approved for patients with hormone receptor (HoR)-positive and HER2-negative metastatic breast cancer (MBC). We aimed to investigate the efficacy, safety, and treatment patterns of chidamide and identify clinicopathological factors that predict the efficacy of chidamide in real-world scenarios.
METHODS
Consecutive MBC patients treated with chidamide from January 2020 to August 2021 across 11 institutions were enrolled in this multicenter, retrospective study. Eligible patients were pre- and postmenopausal women who had clinically or histologically confirmed ER-positive, HER2-negative MBC, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients with multiple primary malignancies or missing baseline characteristics were excluded. Patients received 30 mg chidamide orally twice a week, combined with aromatase inhibitors (AIs) or non-AIs. Efficacy analyses included progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR). Univariate and multivariate Cox regression analyses were performed to identify the potential efficacy predictors.
RESULTS
A total of 157 patients were finally included for analysis. The median number of lines prior to chidamide was four. In the whole cohort, the median PFS was 4.2 months (95% confidence interval [CI] 3.8-4.5). The ORR was 7.5% and the CBR was 31.3%. The efficacy of chidamide was consistent in patients pretreated with CDK4/6 inhibitors and patients treated with different endocrine combinations. Multivariate analysis indicated that patients who had liver metastases (adjusted HR = 1.66, 95% CI 1.14-2.43, adjusted p = 0.008) or ≥3 prior lines of treatment (adjusted HR = 1.80, 95% CI 1.17-2.77, adjusted p = 0.008) had significantly worse PFS. The most common AEs with chidamide were thrombocytopenia, leucopenia, neutropenia, and anemia.
CONCLUSION
This study provided real-world data for the use of chidamide in patients with HoR-positive and HER2-negative MBC. Our data endorsed the use of chidamide in patients pretreated with CDK4/6 inhibitors and patients treated with different endocrine combinations.
Topics: Humans; Female; Breast Neoplasms; Receptor, ErbB-2; Retrospective Studies; Antineoplastic Combined Chemotherapy Protocols; Aminopyridines; Benzamides
PubMed: 38457252
DOI: 10.1002/cam4.6762 -
Chemical Science Mar 2024Terminal rare-earth-metal imide complexes TpLn(NCHiPr-2,6)(dmap) of the mid-late rare-earth elements dysprosium and holmium were synthesized double methane elimination...
Terminal rare-earth-metal imide complexes TpLn(NCHiPr-2,6)(dmap) of the mid-late rare-earth elements dysprosium and holmium were synthesized double methane elimination of Lewis acid stabilized dialkyl precursors TpLnMe(GaMe) with primary aniline derivative HNCHiPr-2,6 (HNAr). Exploiting the weaker Ln-CH⋯[GaMe] interaction compared to the aluminium congener, addition of the aniline derivative leads to the mixed methyl/anilido species TpLnMe(HNAr) which readily eliminate methane after being exposed to the Lewis base DMAP ([double bond, length as m-dash],-dimethyl-4-aminopyridine). Under the same conditions, [AlMe]-stabilized dimethyl rare-earth-metal complexes transform immediately to Lewis acid bridged imides TpLn(μ-NCHMe-2,6)(μ-Me)AlMe (Ln = Dy, Ho). DMAP/THF donor exchange is accomplished by treatment of TpLn(NCHiPr-2,6)(dmap) with 9-BBN in THF while the terminal imides readily insert carbon dioxide to afford carbamate complexes.
PubMed: 38455031
DOI: 10.1039/d3sc06584g