PKI-179: An orally efficacious dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor

A series of mono-morpholino 1,3,5-triazine derivatives (8a–8q) bearing a 3-oxa-8-azabicyclo[3.2.1]octane were prepared and evaluated for PI3-kinase/mTOR activity. Replacement of one of the bis-morpholines in lead compound 1 (PKI-587) with 3-oxa-8-azabicyclo[3.2.1]octane and reduction of the molecular weight yielded 8m (PKI-179), an orally efficacious dual PI3-kinase/mTOR inhibitor. The in vitro activity, in vivo efficacy, and PK properties of 8m are discussed.     

Hematological,biochemical, respiratory,cardiovascular and electroneurophysiological parameters in African green monkeys (Cercopithecus aethiops sabaeus). Its use in non‐clinical toxicological studies

Background The purpose of this study is to better characterize the hematological, biochemical, respiratory, cardiovascular and electroneurophysiological parameters in young adult Cercopithecus aethiops sabaeus of both sexes. The rhesus and cynomolgus monkeys are widely used as experimental primate models. However, only few articles have been published testing toxicological effects of pharmaceuticals on African green monkey. Methods The present study was carried out with the recompilation of all parameters recorded before the first drug administration in five sub‐chronic or chronic toxicological studies performed on 66 Cercopithecus aethiops sabaeus, born in Cuba. Results This study provides hematological, biochemical, respiratory, cardiovascular and electroneurophysiological data for both choosing animals to be included into experiments and monitoring these parameters during the study. Conclusions We conclude that this study provides valuable integrated data for determining the health status, including electroneurophysiological parameters, data not previously reported for this species, of the African green monkey.     

Glyphosate affects lignin content and amino acid production in glyphosate-resistant soybean

Farmers report that some glyphosate-resistant soybean varieties are visually injured by glyphosate. Glyphosate is the main herbicide that directly affects the synthesis of secondary compounds. In this work, we evaluated the effect of increasing rates of glyphosate on lignin and amino acid content, photosynthetic parameters and dry biomass in the early maturity group cultivar BRS 242 GR soybean. Plants were grown in half-strength complete nutrient solution and subjected to various rates of glyphosate either as a single or in sequential applications. All parameters evaluated were affected by increasing glyphosate rates. The effects were more pronounced as glyphosate rates increased, and were more intense with a single total application than sequential applications at lower rates.     

Correlation between loss of pro-chiral hydrogen and E,Z geometry in isoprenoid biosynthesis

Biosynthesis of several mono- and sesqui-terpenes that possess E or Z double bonds, or which are generally considered to be derived from precursors possessing such geometries, involved loss of the pro-4S hydrogen of mevalonate in the construction of the double bond. These results confirm and extend previous observations. A recent claim to have newly discovered such a stereochemical correlation is rejected.     

Dielectric Properties of the Plasma Membrane of Cultured Murine Fibroblasts Treated with a Nonterpenoid Extract of Azadirachta indica Seeds

Neem oil is a natural product obtained from the seeds of the tree Azadirachta indica. In this report, we investigate the alterations of the biophysical properties of the plasma membrane caused by treatment with the nonterpenoid fraction of neem oil that we defined as methanolic extract (MEX). The dose-response effect was evaluated and a MEX-dependent cytoxicity evidenced. The effect of MEX on the plasma membrane was studied by a well-established dielectric spectroscopy technique: electrorotation, which allows single-cell analysis. Our results show a structural/functional alteration of the plasma membrane with an evident increase of specific capacitance and conductance. The biological implications of this effect are discussed.     

Interactions of chlorpromazine with phospholipid monolayers: effects of the ionization state of the drug

Molecular dynamics simulations have been performed to investigate the interactions between chlorpromazine (CPZ) and Langmuir monolayers of the zwitterionic dipalmitoylphosphatidylcholine (DPPC) and the anionic dipalmitoylphosphatidylglycerol (DPPG). Simulations for a fixed surface density and different charge states - neutral and protonated CPZ - were able to capture important features of the CPZ-phospholipid monolayer interaction. Neutral CPZ is predominantly found in the hydrophobic tail region, whereas protonated CPZ is located at the lipid-water interface. Specific interactions (hydrogen bonds) between protonated CPZ and the lipid head groups were found for both zwitterionic and anionic monolayers. We computed lipid tail order parameters and investigated the effects of the drug upon tail ordering. We also computed electrostatic surface potentials and found qualitative good agreement with experimental results.     

Insecticidal effects of Flourensia oolepis Blake (Asteraceae) essential oil

Flourensia oolepis Blake (Asteraceae) essential oil had a complex chemical composition with τ-muurolene (6.14%), santolinetriene (6.22%), 2-methylene-4,8,8-trimethyl-4-vinyl-bicyclo[5.2.0]nonane (10.15%), δ-cadinene (10.27%) and γ-gurjunene (20.69%) comprising more than 50% of the oil. This oil had repellent and toxic effects on Tribolium castaneum Herbst (Coleoptera: Tenebrionidae) adults, acting as a contact toxin. Myzus persicae (Sulzer) (Homoptera: Aphididae) and Leptinotarsa decemlineata Say (Coleoptera: Chrysomelidae) adults showed behavioral sensibility to this oil.     

Mapping the protein interaction network in methicillin-resistant Staphylococcus aureus

Mortality attributable to infection with methicillin-resistant Staphylococcus aureus (MRSA) has now overtaken the death rate for AIDS in the United States, and advances in research are urgently needed to address this challenge. We report the results of the systematic identification of protein-protein interactions for the hospital-acquired strain MRSA-252. Using a high-throughput pull-down strategy combined with quantitative proteomics to distinguish specific from nonspecific interactors, we identified 13,219 interactions involving 608 MRSA proteins. Consecutive analyses revealed that this protein interaction network (PIN) exhibits scale-free organization with the characteristic presence of highly connected hub proteins. When clinical and experimental antimicrobial targets were queried in the network, they were generally found to occupy peripheral positions in the PIN with relatively few interacting partners. In contrast, the hub proteins identified in this MRSA PIN that are essential for network integrity and stability have largely been overlooked as drug targets. Thus, this empirical MRSA-252 PIN provides a rich source for identifying critical proteins essential for network stability, many of which can be considered as prospective antimicrobial drug targets.