Transformations of Ethyl 3-{[1-(Alkoxycarbonyl)-2-(dimethylamino)ethenyl]amino}-2-cyanoprop-2-enoates: Synthesis of Dialkyl 3-Aminopyrrole-2,4-dicarboxylates

The transformation of ethyl 3-{[1-(alkoxycarbonyl)-2-(dimethylamino)ethenyl]amino}2-cyanoprop-2-enoates 2 to dialkyl 3-aminopyrrole-2,4-dicarboxylates 3 in good yields is described.     

Methyl and Phenylmethyl 2-Acetyl-3-{[2-(dimethylamino)-1-(methoxycarbonyl)ethenyl]amino}prop-2-enoate in the Synthesis of heterocyclic systems: Preparation of 3-amino-4H-pyrido-[1,2-a]pyrimidin-4-ones

Methyl 2-acetyl-3-{[2-(dimethylamino)-1-(methoxycarbonyl)ethenyl]amino}prop-2-enoate ( 4 ) and phenyl-methyl 2-acetyl-3-{[2-(dimethylamino)-1(methoxycarbonyl)ethenyl]amino}prop-2-enoate ( 5 ) were prepared in three steps from the corresponding acetoacetic esters, and used as reagents for the preparation of N³-protected 3-amino-4H-pyrido[1,2-a]pyrimidin-4-ones 10 – 12 , 5H-thiazolo[3,2-a]pyrimidin-5-one 13 , 4H-pyrido[1,2-a]-pyridin-4-one 19 and 2H-1-benzopyran-2-ones 20 – 23 . Free 3-amino-4H-pyrido[1,2-a]pyrimidin-4-ones 24 – 26 were prepared from 10 – 12 by removal of the 2-(methoxycarbonyl)-3-oxobut-1-enyl or 3-oxo-2-[(phenyl-methoxy)carbonyl]but-1-envl as N-protecting group by various methods.     

Direct determination of free bilirubin in serum at sub-nanomolar levels

Direct analysis of free bilirubin in human and animal blood serum samples is reported for the first time. A state-of-the-art system comprised of newly developed high-performance liquid chromatography (HPLC) on reverse-phase (RP) C18 support coupled with thermal lens spectrometric detection (TLS), based on excitation at λ = 457.9 nm by an argon laser was used for this purpose. This HPLC-TLS method enabled a baseline separation of all three structural isomers of bilirubin (XIII-α, IX-α and III-α) and the respective degradation products in isocratic mode in fewer than 7 min. The method excels in ultra-high sensitivity with limit of detection (LOD) and limit of quantitation (LOQ) of 90 pM and 250 pM, respectively. Moreover, this method also affords high precision and accuracy, with correlation coefficients R² > 0.997 over a broad linear range (0.250–150 nM) and R² = 0.9998 in a concentration range of clinical interest (0.500–25 nM). The method's boosted sensitivity enabled to streamline sample preparation to just one serum ultrafiltration step, which made qualitative evaluation of sample preparation possible for the first time. The performance of the HPLC-TLS method was assessed to have 20-fold enhanced sensitivity when compared to a comparable method incorporating HPLC coupled with diode array detector (DAD), which is also a novel method by itself, and could be applied for free bilirubin determination in patients with elevated bilirubin levels.     

The influence of temperature on rheological properties of blood mixtures with different volume expanders—implications in numerical arterial hemodynamics simulations

During the complicated cardiac surgery on a non-beating heart with cardiopulmonary bypass, protection of the heart is accomplished by injecting cold cardioplegic solutions. In most forms of circulatory shock, it is necessary to immediately restore the circulating volume. Intravenous solutions of volume expanders, such as hydroxyethyl starch and dextrans, are used to increase the volume of fluid in the circulating blood. In this work, blood samples of six donors were obtained and used to prepare mixtures with different volume expanders in concentrations ranging from 10 to 50 vol./vol.%. The flow curves of all mixtures in the temperature range from 4°C to 37°C were constructed and fitted to the Herschel–Bulkley model, in order to extract the shear thinning and yield stress parameters. To assess the influence of the observed changes in the rheological properties of blood on the hemodynamics in arterial vasculature, a realistic three-dimensional rigid-wall computational model was constructed from MRI images of the right carotid bifurcation obtained in vivo from a healthy male volunteer. The time-varying flow field was numerically computed using the Newtonian model as well as the Herschel–Bulkley model with the Papanastasiou regularization. The numerical simulations indicate only moderate changes in the time-averaged flow field that become accentuated when the instantaneous flow field is considered. We also found that although the influence of temperature, hematocrit, and volume expanders on hemodynamics is significant, this can primarily be attributed to the changes in the nominal viscosity of the flow medium.     

Self-similar scaling of density in complex real-world networks

Despite their diverse origin, networks of large real-world systems reveal a number of common properties including small-world phenomena, scale-free degree distributions and modularity. Recently, network self-similarity as a natural outcome of the evolution of real-world systems has also attracted much attention within the physics literature. Here we investigate the scaling of density in complex networks under two classical box-covering renormalizations–network coarse-graining–and also different community-based renormalizations. The analysis on over 50 real-world networks reveals a power-law scaling of network density and size under adequate renormalization technique, yet irrespective of network type and origin. The results thus advance a recent discovery of a universal scaling of density among different real-world networks [P.J. Laurienti, K.E. Joyce, Q.K. Telesford, J.H. Burdette, S. Hayasaka, Universal fractal scaling of self-organized networks, Physica A 390 (20) (2011) 3608–3613] and imply an existence of a scale-free density also within–among different self-similar scales of–complex real-world networks. The latter further improves the comprehension of self-similar structure in large real-world networks with several possible applications.     

A Simple Stereoselective Synthesis of Aplysinopsin Analogs

Simple and stereoselective syntheses of aplysinopsins and their analogs from either methyl 2‐[(2,2‐disubstituted ethenyl)amino]‐3‐(dimethylamino)prop‐2‐enoates 11 or 5‐[(dimethylamino)methylidene]imidazolidine‐2,4‐diones 20 are described. The structures of products are established by ¹H‐ and ¹³C‐NMR, and NOESY spectroscopy, and X‐ray crystal‐structure analysis.     

Methyl 2-[bis(acetyl)ethenyl]aminopropenoate in the synthesis of heterocyclic systems

Methyl 2-[bis(acetyl)ethenyl]aminopropenoate ( 4 ) was prepared in 3 steps from acetylacetone ( 1 ) via 4-(N,N-dimethylamino)-3-acetylbut-3-en-2-one ( 2 ) and methyl N-[2,2-bis(acetyl)ethenyl]glycinate ( 3 ). Compound 4 reacts with N- and C-nucleophiles to give fused heterocyclic systems. Derivatives of pyrido[1,2-a]pyrimidones 14–16 and thiazolo[3,2-a]pyrimidones 17 and 18 were prepared from 2-aminopyridines and 2-aminothiazoles, respectively. With C-nucleophiles derivatives of pyrido[1,2-a]-pyridinone 19 and 2H-1-benzopyran-2-one 20–22 were prepared.     

In Vivo Imaging of Mouse Tumors by a Lipidated Cathepsin S Substrate

The synthesis and evaluation of two cathepsin S‐specific probes is described. For long‐term retention of the probe at the target site and a high signal‐to‐noise ratio, we introduced a lipidation approach via the simple attachment of palmitoic acid to the reporter. After cathepsin S‐specific cleavage in cultured cells and in a grafted tumor mouse model, fluorescence increased owing to dequenching and we observed an intracellular accumulation of the fluorescence in the target tissue. The lipidated probe provided a prolonged and strongly fluorescent signal in tumors when compared to the very similar non‐lipidated probe, demonstrating that non‐invasive tumor identification is feasable. The homing principle by probe lipidation might also work for selective administration of cytotoxic compounds to specifically reduce tumor mass.     

Direct synthesis of arenecarboxamides through Friedel–Crafts acylation using ureas

The reaction of urea derivatives that contain the phenothiazine unit with trifluoromethanesulfonic anhydride in the presence of electron-rich aromatic compounds leads to the formation of arenecarboxamides. The reaction has been successfully demonstrated for several inter- and intramolecular systems.