β-amino alcohols and their respective 2-phenyl-N-alkyl aziridines as potential DNA minor groove binders

It is known that aziridines and nitrogen mustards exert their biological activities, especially in chemotherapy, via DNA alkylation. The studied scaffold, 2-phenyl-1-aziridine, provides a distinct conformation compared to commonly used aziridines, and therefore, leads to a change in high-strained ring reactivity towards biological nucleophiles, such as DNA. The above series of compounds was tested in three breast cell lines: MCF-10, a healthy cell; MCF-7, a hormone responsive cancer cell; and MDA-MB-231, a triple negative breast cancer cell. Both aziridines and their precursors, β-amino alcohols, showed activity towards these cells, and some of the compounds showed higher selectivity index than cisplatin, the drug used as control. When the type of cell death was investigated, the synthesized compounds demonstrated higher apoptosis and lower necrosis rates than cisplatin, and when the mechanism of action was studied, the compounds were shown to interact with DNA via its minor groove instead of alkylation or intercalation

Role of spinon and spinon singlet pair excitations on phase transitions in d−waved-wave superconductors

We examine the roles of massless Dirac spinon and spin singlet pair excitations on the phase transition in $d-wave$ superconductors. Although the massless spinon excitations in the presence of the spin singlet pair excitations do not alter the nature of the phase transition at $T = 0$, that is, the XY universality class, they are seen to induce an additional attractive interaction potential between vortices, further stabilizing vortex-antivortex pairs at low temperature for lightly doped high $T_c$ samples.Comment: 5 pages, 1 figur

Lapachol, a compound targeting pyrimidine metabolism, ameliorates experimental autoimmune arthritis

Abstract\ud \ud Background\ud The inhibition of pyrimidine biosynthesis by blocking the dihydroorotate dehydrogenase (DHODH) activity, the prime target of leflunomide (LEF), has been proven to be an effective strategy for rheumatoid arthritis (RA) treatment. However, a considerable proportion of RA patients are refractory to LEF. Here, we investigated lapachol (LAP), a natural naphthoquinone, as a potential DHODH inhibitor and addressed its immunosuppressive properties.\ud \ud \ud Methods\ud Molecular flexible docking studies and bioactivity assays were performed to determine the ability of LAP to interact and inhibit DHODH. In vitro studies were conducted to assess the antiproliferative effect of LAP using isolated lymphocytes. Finally, collagen-induced arthritis (CIA) and antigen-induced arthritis (AIA) models were employed to address the anti-arthritic effects of LAP.\ud \ud \ud Results\ud We found that LAP is a potent DHODH inhibitor which had a remarkable ability to inhibit both human and murine lymphocyte proliferation in vitro. Importantly, uridine supplementation abrogated the antiproliferative effect of LAP, supporting that the pyrimidine metabolic pathway is the target of LAP. In vivo, LAP treatment markedly reduced CIA and AIA progression as evidenced by the reduction in clinical score, articular tissue damage, and inflammation.\ud \ud \ud Conclusions\ud Our findings propose a binding model of interaction and support the ability of LAP to inhibit DHODH, decreasing lymphocyte proliferation and attenuating the severity of experimental autoimmune arthritis. Therefore, LAP could be considered as a potential immunosuppressive lead candidate with potential therapeutic implications for RA.The research leading to these results received funding from the European\ud Union Seventh Framework Programme (FP7-2007-2013) under grant\ud agreement n° HEALTH-F4-2011-281608 (TIMER), from the São Paulo Research\ud Foundation (FAPESP) under grant agreements n° 2009/54014-7, 2011/1967-0,\ud 2012/25075-0, 2014/50265-3, 2012/20990-2 and 2013/08216-2 (Center for\ud Research in Inflammatory Diseases), and from the University of São Paulo\ud NAP-DIN and NPPNS under grant agreement n° 11.1.21625.01.0 and\ud 2012.1.17587.1.1, respectivel

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Fluorescence Quenching of Two meso

Ferric ion (Fe(III)) is a biologically and environmentally relevant cation so that its analysis in environmental and biological samples is often required. Borodiazaindacenes (BODIPYs) are known for their good photophysical properties; however, there are few BODIPY-based Fe(III) sensors reported. Herein, we show the characterisation of two BODIPY dyes whose fluorescence emission is diminished by such cation. Both "turn-off" probes, a catecholyl-substituted BODIPY and a pyridyl-substituted BODIPY, were synthetically obtained and an initial screening showed a relatively good specificity for Fe(III) when compared to other cations. Catecholyl-substituted BODIPY was more sensitive to Fe(III), however, with a pH-dependent analytical performance and low brightness. On the other hand, pyridyl-substituted BODIPY was very bright and its analytical performance was apparently pH-independent, however, it was less sensitive to the analyte. In conclusion, we show herein the obtainment and characterisation of two probes with promising analytical value in the analysis of Fe(III)

Oral administration of peptide-based drugs: Beyond Lipinski's rule

The use of peptides in therapy presents several limitations, from physicochemical characteristics to inadequate pharmacokinetic profiles for oral absorption. As peptides are gaining importance in the therapeutic arsenal, there is an increasing need to rationalize the main characteristics of this compound class in the market. Therefore, we performed an extensive analysis of all known peptide drugs and clinical candidates based on their peptide features, physicochemical and structural properties, and correlated these with their administration route and therapeutic classes. Peptide drugs are widely distributed across drug and pharmacological space, covering several therapeutic areas with structural diversity and complexity, distributed between groups of cyclic and linear compounds. Although structural and physicochemical properties are clear within these groups, we counter the consensus that cyclic peptides have better oral availability than linear peptides, as most of the orally administrated peptides have linear structures. This study and review furnishes information that could support peptide drug design, with a new cutoff of known descriptors that go beyond the Rule of Five

Fragmentation studies and electrospray ionization mass spectrometry of lapachol: protonated, deprotonated and cationized species

Electrospray ionization mass spectrometric analysis of lapachol (2-hydroxy-3-(3-methy1-2-butenyl)-1,4-naphthoquinone) was accomplished in order to elucidate the gas-phase dissociation reactions of this important biologically active natural product. The occurrence of protonated and cationized species in the positive mode and of deprotonated species in the negative mode was explored by means of collision-induced dissociation (CID) experiments. For the protonated molecule, the H(2)O and C(4)H(8) losses occur by two competitive channels. For the deprotonated molecule, the even-electron rule is not conserved, and the radicalar species are eliminated by formation of distonic anions. The fragmentation mechanism for each ion was suggested on the basis of computational thermochemistry. Atomic charges, relative energies, and frontier orbitals were employed aiming at a better understanding of the gas-phase reactivity of lapachol. Potential energy surfaces for fragmentation reactions were obtained by the B3LYP/6-31+G(d,p) model. Copyright (C) 2010 John Wiley & Sons, Ltd.FAPESP[05/01572-1]FAPESP[2009/14184-0]FAPESP[2009/51812]CAPES[09/08281-3]CNPqINCT-i

Thiocyanation of 3-substituted and 3,5-disubstituted BODIPYs and its application for the synthesis of new fluorescent sensors

© 2018 Elsevier Ltd Interest in BODIPYs (acronym of boron dipyrromethene) has skyrocketed in recent decades, mainly due to their favourable photophysical properties and the wide range of functionalization methods reported for these organic fluorescent dyes. In this context, a simple and straightforward method for the direct thiocyanation of 1,3,5,7-tetramethy-BODIPYs using ammonium thiocyanate and oxone was recently reported as an alternative for the preparation of thiocyanated and thioalkylated BODIPYs. Herein, we performed the thiocyanation of 3-substituted and 3,5-disubstituted BODIPY dyes, which were synthesized from the nucleophilic substitution of halogenated precursors with morpholine, propanethiol and sodium methoxide. There was a direct relation between the electron-donating character of the substituent and the yields of the thiocyanated BODIPYs, which gives support to a mechanism based on the electrophilic substitution by a thiocyanogen species formed in situ. Spectroscopic and photophysical characterization of these new fluorophores was performed and included bidimensional NMR, UV/vis absorption, fluorescence emission and fluorescence quantum yields. The photophysical properties are highly dependable on the structural features of each dye. While 3-morpholino-8-phenyl BODIPYs are virtually non-fluorescent, the fluorescence quantum yields of 3-(4-methoxybenzylamino)-8-methyl BODIPYs were close to 0.9. The thiocyanation of BODIPYs can result in interesting photophysical shifts that can be explored in the fine-tuning of fluorescent sensors. We also report the results of a preliminary qualitative analysis that indicates interesting bathochromic or hypsochromic shifts on the absorption and fluorescence emission spectra when some of the highly emissive dyes were treated with strong acid.status: publishe

Synthesis of Some Functionalized Peptomers via Ugi Four-Component Reaction

<div><p></p><p>This article describes the synthesis of new peptomers through a simple and efficient route using a one-pot Ugi four-component reaction. The synthesis started from either carboxylic acids or protected amino acids, primary amines, aldehydes, and isocyanides in anhydrous methanol and proceeded under stirring at room temperature. The reaction produced several functionalized peptomers in good yields (67–80%). These compounds are versatile multifunctional intermediates that can be further unprotected or functionalized to generate new molecules with numerous applications in the field of biomedicine.</p></div