Reversal of diastereoselectivity in the synthesis of Peptidomimetic 3‑Carboxamide-1,4-benzodiazepin-5-ones

Enantiopure 3-carboxamide-1,4-benzodiazepin-5-ones were synthesized via the Ugi reaction followed by the Staudinger/aza-Wittig or reduction reactions in only two steps. A complete reversal of diastereoselectivity was achieved depending on the cyclization methodology employed. The different orientation of the C3 substituent in our 3-substituted 1,4-benzodiazepin-5-ones with respect to the most studied 1,4-benzodiazepin-2-ones makes them complementary in the development of new drugs because the primary source of binding selectivity of 1,4-benzodiazepines is the selective recognition of ligand conformations by the receptor.Ministerio de Economía y Competitividad, Spain (Project CTQ2012-31611), Junta de Castilla y León, Consejería de Educación y Cultura y Fondo Social Europeo (Project BU246A12-1) and the European Commission, Seventh Framework Programme (Project SNIFFER FP7-SEC-2012-312411)

Pre-clinical pharmacology and mechanism of action of SG3199, the pyrrolobenzodiazepine (PBD) dimer warhead component of antibody-drug conjugate (ADC) payload tesirine

Synthetic pyrrolobenzodiazepine (PBD) dimers, where two PBD monomers are linked through their aromatic A-ring phenolic C8-positions via a flexible propyldioxy tether, are highly efficient DNA minor groove cross-linking agents with potent cytotoxicity. PBD dimer SG3199 is the released warhead component of the antibody-drug conjugate (ADC) payload tesirine (SG3249), currently being evaluated in several ADC clinical trials. SG3199 was potently cytotoxic against a panel of human solid tumour and haematological cancer cell lines with a mean GI50 of 151.5 pM. Cells defective in DNA repair protein ERCC1 or homologous recombination repair showed increased sensitivity to SG3199 and the drug was only moderately susceptible to multidrug resistance mechanisms. SG3199 was highly efficient at producing DNA interstrand cross-links in naked linear plasmid DNA and dose-dependent cross-linking was observed in cells. Cross-links formed rapidly in cells and persisted over 36 hours. Following intravenous (iv) administration to rats SG3199 showed a very rapid clearance with a half life as short as 8 minutes. These combined properties of cytotoxic potency, rapid formation and persistence of DNA interstrand cross-links and very short half-life contribute to the emerging success of SG3199 as a warhead in clinical stage ADCs

Impaired Executive Function Mediates the Association between Maternal Pre-Pregnancy Body Mass Index and Child ADHD Symptoms

Increasing evidence suggests exposure to adverse conditions in intrauterine life may increase the risk of developing attention-deficit/hyperactivity disorder (ADHD) in childhood. High maternal pre-pregnancy body mass index (BMI) has been shown to predict child ADHD symptoms, however the neurocognitive processes underlying this relationship are not known. The aim of the present study was to test the hypothesis that this association is mediated by alterations in child executive function.A population-based cohort of 174 children (mean age = 7.3 ± 0.9 (SD) yrs, 55% girls) was evaluated for ADHD symptoms using the Child Behavior Checklist, and for neurocognitive function using the Go/No-go task. This cohort had been followed prospectively from early gestation and birth through infancy and childhood with serial measures of maternal and child prenatal and postnatal factors. Maternal pre-pregnancy BMI was a significant predictor of child ADHD symptoms (F((1,158)) = 4.80, p = 0.03) and of child performance on the Go/No-go task (F((1,157)) = 8.37, p = 0.004) after controlling for key potential confounding variables. A test of the mediation model revealed that the association between higher maternal pre-pregnancy BMI and child ADHD symptoms was mediated by impaired executive function (inefficient/less attentive processing; Sobel Test: t = 2.39 (± 0.002, SEM), p = 0.02).To the best of our knowledge this is the first study to report that maternal pre-pregnancy BMI-related alterations in child neurocognitive function may mediate its effects on ADHD risk. The finding is clinically significant and may extrapolate to an approximately 2.8-fold increase in the prevalence of ADHD among children of obese compared to those of non-obese mothers. These results add further evidence to the growing awareness that neurodevelopmental disorders such as ADHD may have their foundations very early in life

Oxidative stress in the developing brain: effects of postnatal glucocorticoid therapy and antioxidants in the rat.

In premature infants, glucocorticoids ameliorate chronic lung disease, but have adverse effects on long-term neurological function. Glucocorticoid excess promotes free radical overproduction. We hypothesised that the adverse effects of postnatal glucocorticoid therapy on the developing brain are secondary to oxidative stress and that antioxidant treatment would diminish unwanted effects. Male rat pups received a clinically-relevant tapering course of dexamethasone (DEX; 0.5, 0.3, and 0.1 mg x kg(-1) x day(-1)), with or without antioxidant vitamins C and E (DEXCE; 200 mg x kg(-1) x day(-1) and 100 mg x kg(-1) x day(-1), respectively), on postnatal days 1-6 (P1-6). Controls received saline or saline with vitamins. At weaning, relative to controls, DEX decreased total brain volume (704.4±34.7 mm(3) vs. 564.0±20.0 mm(3)), the soma volume of neurons in the CA1 (1172.6±30.4 µm(3) vs. 1002.4±11.8 µm(3)) and in the dentate gyrus (525.9±27.2 µm(3) vs. 421.5±24.6 µm(3)) of the hippocampus, and induced oxidative stress in the cortex (protein expression: heat shock protein 70 [Hsp70]: +68%; 4-hydroxynonenal [4-HNE]: +118% and nitrotyrosine [NT]: +20%). Dexamethasone in combination with vitamins resulted in improvements in total brain volume (637.5±43.1 mm(3)), and soma volume of neurons in the CA1 (1157.5±42.4 µm(3)) and the dentate gyrus (536.1±27.2 µm(3)). Hsp70 protein expression was unaltered in the cortex (+9%), however, 4-HNE (+95%) and NT (+24%) protein expression remained upregulated. Treatment of neonates with vitamins alone induced oxidative stress in the cortex (Hsp70: +67%; 4-HNE: +73%; NT: +22%) and in the hippocampus (NT: +35%). Combined glucocorticoid and antioxidant therapy in premature infants may be safer for the developing brain than glucocorticoids alone in the treatment of chronic lung disease. However, antioxidant therapy in healthy offspring is not recommended

Collateral Damage: Educational Attainment and Labor Market Outcomes Among German War and Post-War Cohorts

We use data from the West German 1970 census to explore the link between being born during or shortly after World War II and educational and labor market outcomes 25 years later. We document, for the first time, that men and women born in the relatively short period between November 1945 and May 1946 have significantly and substantially lower educational attainment and occupational status than cohorts born shortly before or after. Several alternative explanations for this new finding are put to test. Most likely, a short but severe spell of quantitative and qualitative malnutrition immediately around the end of the war has impaired intrauterine conditions in first trimester pregnancies and resulted in longterm detriments among the affected cohorts. This conjecture is corroborated by evidence from Austria

Association between maternal nutritional status in pregnancy and offspring cognitive function in childhood and adolescence; a systematic review

Background The mother is the only source of nutrition for fetal growth including brain development. Maternal nutritional status (anthropometry, macro- and micro-nutrients) before and/or during pregnancy is therefore a potential predictor of offspring cognitive function. The relationship of maternal nutrition to offspring cognitive function is unclear. This review aims to assess existing evidence linking maternal nutritional status with offspring cognitive function. Methods Exposures considered were maternal BMI, height and weight, micronutrient status (vitamins D, B12, folate and iron) and macronutrient intakes (carbohydrate, protein and fat). The outcome was any measure of cognitive function in children aged <18 years. We considered observational studies and trials with allocation groups that differed by single nutrients. We searched Medline/PubMed and the Cochrane Library databases and reference lists of retrieved literature. Two reviewers independently extracted data from relevant articles. We used methods recommended by the Centre for Reviews and Dissemination, University of York and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Results Of 16,143 articles identified, 38 met inclusion criteria. Most studies were observational, and from high-income settings. There were few randomized controlled trials. There was consistent evidence linking maternal obesity with lower cognitive function in children; low maternal BMI has been inadequately studied. Among three studies of maternal vitamin D status, two showed lower cognitive function in children of deficient mothers. One trial of folic acid supplementation showed no effects on the children’s cognitive function and evidence from 13 observational studies was mixed. Among seven studies of maternal vitamin B12 status, most showed no association, though two studies in highly deficient populations suggested a possible effect. Four out of six observational studies and two trials (including one in an Iron deficient population) found no association of maternal iron status with offspring cognitive function. One trial of maternal carbohydrate/protein supplementation showed no effects on offspring cognitive function. Conclusions Current evidence that maternal nutritional status during pregnancy as defined by BMI, single micronutrient studies, or macronutrient intakes influences offspring cognitive function is inconclusive. There is a need for more trials especially in populations with high rates of maternal undernutrition. Systematic review registration Registered in PROSPERO CRD42013005702

Synthesis of DNA-Interactive Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs)

Pyrrolobenzodiazepines (PBD) are an important class of sequence-selective DNA-interactive agents that bind covalently to guanine bases within the minor groove of DNA. The PBD monomers are remarkable in possessing a 3-dimensional shape that allows them to fit perfectly within the minor groove of DNA, partly due to the longitudinal twist created by the chiral center at their C11a-position. A PBD produced synthetically, semisynthetically, or isolated from natural sources can exist as a mixture of two or even three forms or can exist predominantly as just one. Various biochemical and structural studies on PBD-DNA adducts have suggested that the molecules locate themselves with their N10-position pointing toward the floor of the minor groove. A further important feature of the PBDs is that they interact selectively with specific DNA sequences. A significant effort has also been made to increase the base-pair span and sequence-selectivity of PBD molecules so that they might be used as gene-targeting agents in biological experiments and possibly as therapeutic agents

Sea-ice transport of riverine particles from the Laptev Sea to Fram Strait based on clay mineral studies

The aim of this study was to identify pathways and processes of modern sediment transport from the Siberian hinterland to the Laptev Sea and further to the Arctic Ocean. Clay mineral analyses were performed on riverine suspended particulate material (SPM), surface sediments of the Laptev Sea shelf, and sea-ice sediments (SIS). Material collected during seven expeditions was included in this study. Clay mineral assemblages are used to decipher the distribution of riverine sediments on the shallow Laptev Sea shelf, the entrainment of fine particles into newly forming ice, and the transport of SIS from the Laptev Sea towards the ablation areas. A cluster analysis of our data set shows that the clay mineral assemblages of Laptev Sea shelf sediments and SIS are controlled mainly by the input of riverine SPM supplied by the Khatanga, Lena, and Yana Rivers. Whereas the western shelf clay-mineral province is characterized by enhanced smectite concentrations supplied by the Khatanga River, the eastern Laptev Sea is dominated by illite discharged through the Lena and Yana Rivers. The SIS smectite concentration serves as an indicator for sediment source areas on the circum-Arctic shelves. Subsequently, the Transpolar Drift can be distinguished into a Siberian Branch fed from the eastern Kara Sea and the western Laptev Sea, and a Polar Branch originating from the eastern Laptev Sea

Parallel Synthesis of a Novel C2-Aryl Pyrrolo[2,1-c][1,4]benzodiazepine (PBD) Library

A 66-member C2-aryl pyrrolo[2,1-c][1,4]benzodiazepine (PBD) library has been successfully synthesized in parallel via Suzuki coupling using PS-PPh3Pd (catalyst) and PS-DEAM (scavenger) under microwave radiation. Library members were obtained in sufficient yield (up to 91%) and purity (85-98% crude) for biological evaluation