Chiral Recognition of Flexible Melatonin Receptor Ligands Induced by Conformational Equilibria

N-anilinoethylamides are a class of melatoninergic agents with the aniline portion mimicking the indole ring of the natural ligand and the ethylamide chain reproducing that of melatonin. The simplest compound in this class, N-{2-[(3-methoxyphenyl)methylamino]ethyl}acetamide (UCM793), has nanomolar binding affinity for MT1 and MT2 membrane receptors. To explore the effect of chain conformation on receptor binding, a methyl group was inserted on the methylene alpha or beta to the amide nitrogen and conformational equilibria were investigated by NMR spectroscopy and molecular dynamics simulations. Receptor affinity was conserved only for the beta-methyl derivative, which also showed significant stereoselectivity, with the (S) enantiomer being the eutomer. Molecular dynamics simulations, validated by NMR spectroscopy, showed that the beta-methyl group affects the conformational preferences of the ethylamide chain. Docking into the receptor crystal structure provides a rationale for the observed chiral recognition, suggesting that the (S)-beta-methyl group favors the conformation that better fits the receptor binding site

Essential Oil Chemical Composition, Antioxidant and Antibacterial Activities of Eucalyptus largiflorens F. Muell

In this study, we investigated the chemical composition, the antibacterial activity, and the antioxidant properties of extracts obtained from the leaves, flowers, and fruits of Eucalyptus largiflorens F. Muell. The antioxidant effects of the methanolic extract of aerial parts of the plant, obtained by Soxhlet apparatus, were estimated using 1,1-diphenyl-2-picrylhydrazyl (DPPH) and β-carotene/linoleic acid methods. The essential oils were chemically characterized by gas chromatography (GC) coupled with mass spectrometry (MS) and flame ionization detector (FID). Thirty compounds were identified, with 1,8-cineol, α-pinene, aromadendrene, globulol and α-phellandrene being the major components. The antibacterial activities of the essential oils were tested against several bacterial isolates, including Staphylococcus aureus, Staphylococcus epidermidis and Escherichia Coli, using the disc diffusion method. All the essential oils exhibited antibacterial activity. The maximum zone of inhibition was observed for Escherichia coli, with the fruit essential oil in the concentration (100 μL). There was no significant antioxidant activity in the essential oils, while the extracts exhibited considerable antioxidant effects in comparison to butylated hydroxytoluene (BHT). In this regard, the flower extract showed the highest antioxidant activity in both DPPH (IC50 = 21.5±0.2 μg/mL) and β-carotene/linoleic acid tests (Inhibition (%) = 84.3±0.7). Finally, the fruit essential oil exerts a significant antibacterial activity against several bacterial strains and exhibits a significant antioxidant effect in the β-carotene/linoleic acid tests, thus it may represent an innovative nutraceutical tool able to act on bacteria and host oxidative stress related to infections

Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P < .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients

An improved synthesis of cis-4-phenyl-2-propionamidotetralin (4-P-PDOT): a selective MT2 melatonin receptor antagonist.

A novel, efficient and diastereoselective procedure was developed for the gram-scale synthesis of cis-4-phenyl-2-propionamidotetralin (4-P-PDOT), a selective MT2melatonin receptor antagonist. The synthetic strategy involved the conversion of 4-phenyl-2-tetralone to enamide followed by diastereoselective reduction affording cis-4-P-PDOT in good yield. The mechanism of the reduction step was explored by employing deuterated reagents

Organocatalyzed coupling of indoles with dehydroalanine esters: synthesis of bis(indolyl)propanoates and indolacrylates

Functionalized and substituted bis(indolyl)alkanes were synthesized from indoles and dehydroalanine esters in the presence of catalytic amounts of Brønsted acid. When 2- or 4-bulky substituted indoles were used, unusual elimination occurred to yield interesting indolyl acrylates