Human Lanosterol 14-Alpha Demethylase (CYP51A1) Is a Putative Target for Natural Flavonoid Luteolin 7,3′-Disulfate

Widespread pathologies such as atherosclerosis, metabolic syndrome and cancer are associated with dysregulation of sterol biosynthesis and metabolism. Cholesterol modulates the signaling pathways of neoplastic transformation and tumor progression. Lanosterol 14-alpha demethylase (cytochrome P450(51), CYP51A1) catalyzes one of the key steps in cholesterol biosynthesis. The fairly low somatic mutation frequency of CYP51A1, its druggability, as well as the possibility of interfering with cholesterol metabolism in cancer cells collectively suggest the clinical importance of CYP51A1. Here, we show that the natural flavonoid, luteolin 7,3′-disulfate, inhibits CYP51A1 activity. We also screened baicalein and luteolin, known to have antitumor activities and low toxicity, for their ability to interact with CYP51A1. The K_d values were estimated using both a surface plasmon resonance optical biosensor and spectral titration assays. Unexpectedly, in the enzymatic activity assays, only the water-soluble form of luteolin—luteolin 7,3′-disulfate—showed the ability to potently inhibit CYP51A1. Based on molecular docking, luteolin 7,3′-disulfate binding suggests blocking of the substrate access channel. However, an alternative site on the proximal surface where the redox partner binds cannot be excluded. Overall, flavonoids have the potential to inhibit the activity of human CYP51A1 and should be further explored for their cholesterol-lowering and anti-cancer activity.     

Essential oil of Nepeta x faassenii Bergmans ex Stearn (N. mussinii Spreng. x N. nepetella L.): a comparison study

Analysis (GC and GC/MS) of an essential oil sample obtained from dry leaves of Nepeta x faassenii Bergmans ex Steam, a hybrid species produced by crossbreeding N. mussinii Spreng. with N. nepetella L., led to the identification of 109 constituents that represented 95.9% of the oil. The major constituents were 4aalpha,7alpha,7aalpha-nepetalactone (67.8%), 1,8-cineole (6.6%), germacrene D (4.8%), beta-pinene (2.7%), (E)-beta-ocimene (2.6%), 4aalpha,7beta,7aalpha-nepetalactone (2.3%) and (E)-beta-farnesene (1.0%). Chemical composition of the oil was compared, using multivariate statistical analyses (MVA) with those of the oils of other Nepeta taxa, in particular N. mussinii and N. nepetella. This was done in order to explore the mode of inheritance of the monoterpene biosynthetic apparatus of N. faassenii. Chemical composition of the volatiles of a Nepeta taxon (different populations) can be subject to variation due to environmental and geographical factors. To accommodate this fact in the MVAs, along side with N. faassenii essential oil, additional 6 oils (3 different populations of N. nuda L. and N. cataria L. from Serbia) were included in this study (isolated and analyzed (chemically and statistically)). The MVA analyses recognized N. faassenii as being closely related to both N. mussinii and N. nepetella. If the relative content of oil constituents per plant and not per chromatogram were used as variables in the MVA (this was done by simple multiplication of the yields and relative percentages of components) a higher degree of mutual similarity (in respect to the monoterpene biosynthesis) of N. faassenii to N. mussinii, than to the other parent species, was observed.     

Phenyl α-bromovinyl sulfone in cycloadditions with azomethine ylides: an unexpected facile aromatization of the cycloadducts into pyrroles

Phenyl α-bromovinyl sulfone reacts with glycine ester Schiff bases regioselectively in the presence of catalytic amounts of AgOAc and DBU yielding polysubstituted pyrrolidine cycloadducts. Utilization of excess DBU induces subsequent facile aromatization of the cycloadducts and affords 5-arylpyrrole-2-carboxylic acid esters in 39-85% yields in a single step.     

Direct formylation of 2-pyridone core of 3-N-methylcytisine via Duff reaction; synthesis of 9-enyl, 9-ynyl and 9-imino derivatives

The first direct synthesis of 3-N-methyl-9-formylcytisine via electrophylic formylation is described. It is established, that Vilsmeier-Haack and Gatterman variants of this reaction are unsuccessful in the case with 3-substituted (-)-cytisine derivatives, but Duff procedure (with hexamethylenetetramine in trifluoroacetic acid) gives a possibility to obtain the target pseudo aromatic aldehyde with the 69% yield. Convenient precursors for [4 + 2]- or [3 + 2]-cycloaddition reactions are obtained by means of condensation of synthesized 3-N-methyl-9-formylcytisine with acetone, nitromethane and phosphorous ylides with yields from 70 to 87%. Alternative aprroach to alkenyl products and to 9-alkynyl-3-methylcytisine is realized using the Heck and Sonogashira cross-coupling reactions of methyl vinyl ketone, cyclohexenone or trimethylsilylacetylene with 9-bromo-3-methylcytisine (55, 70 and 60% accordingly). It is shown, that interaction of 3-N-methyl-9-formylcytisine with hydroxylamines leads to corresponding nitrone (93%) and oxime (70%). All individual compounds are isolated by column chromatography and completely characterized on the basis of NMR spectroscopy data.     

More Causes Less Effect: Destructive Interference in Decision Making

We present a new experiment demonstrating destructive interference in customers’ estimates of conditional probabilities of product failure. We take the perspective of a manufacturer of consumer products and consider two situations of cause and effect. Whereas, individually, the effect of the causes is similar, it is observed that when combined, the two causes produce the opposite effect. Such negative interference of two or more product features may be exploited for better modeling of the cognitive processes taking place in customers’ minds. Doing so can enhance the likelihood that a manufacturer will be able to design a better product, or a feature within it. Quantum probability has been used to explain some commonly observed “non-classical” effects, such as the disjunction effect, question order effect, violation of the sure-thing principle, and the Machina and Ellsberg paradoxes. In this work, we present results from a survey on the impact of multiple observed symptoms on the drivability of a vehicle. The symptoms are assumed to be conditionally independent. We demonstrate that the response statistics cannot be directly explained using classical probability, but quantum formulation easily models it, as it allows for both positive and negative “interference” between events. Since quantum formalism also accounts for classical probability’s predictions, it serves as a richer paradigm for modeling decision making behavior in engineering design and behavioral economics.     

The temperature dependence of the electrical resistivity and the negative magnetoresistance of carbon nanoparticles

Temperature dependences of the electrical resistivity of samples of carbon nanoparticles obtained from nanodiamonds by annealing at 1800, 1900, and 2140 K were studied. The magnetoresistance of these samples was measured at 4.5 K. Data on the positive magnetoresistance obtained in fields above 3 T were used to estimate the mean free path l of carriers at liquid-helium temperature, l～12 Å for a sample annealed at 1800 K, l～80 Å for a sample annealed at 1900 K, and l～18 Å for the case of annealing at 2140 K. The samples annealed at 1800 and 2140 K exhibit a negative magnetoresistance in fields below 2 T. The carrier concentrations n in the samples annealed at 1800 and 2140 K were estimated as n～8×10²¹ and 3×10²¹ cm^?3, respectively.