Retinoidal pyrimidinecarboxylic acids. Unexpected diaza-substituent effects in retinobenzoic acids

Several pyridine- and pyrimidine-carboxylic acids were synthesized as ligand candidates for retinoid nuclear receptors, retinoic acid receptors (RARs) and retinoic X receptors (RXRs). Although the pyridine derivatives, 6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]pyri dine-3-carboxylic acid (2b) and 6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido]py ridine-3-carboxylic acid (5b) are more potent than the corresponding benzoic acid-type retinoids, Am80 (2a) and Am580 (5a), the replacement of the benzene ring of Am580 (5a), Am555 (6a), or Am55 (7a) with a pyrimidine ring caused loss of the retinoidal activity both in HL-60 cell differentiation assay and in RAR transactivation assay using COS-1 cells. On the other hand, pyrimidine analogs (PA series, 10 and 11) of potent RXR agonists (retinoid synergists) with a diphenylamine skeleton (DA series, 8 and 9) exhibited potent retinoid synergistic activity in HL-60 cell differentiation assay and activated RXRs. Among the synthesized compounds, 2-[N-n-propyl-N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)a mino]pyrimidine-5-carboxylic acid (PA013, 10e) is most active retinoid synergist in HL-60 assay.     

Determination of optimum processing temperature for transformation of glyceryl monostearate

The purpose of this study was to clarify the mechanism of transformation from alpha-form to beta-form via beta'-form of glyceryl monostearate (GM) and to determine the optimum conditions of heat-treatment for physically stabilizing GM in a pharmaceutical formulation. Thermal analysis repeated twice using a differential scanning calorimeter (DSC) were performed on mixtures of two crystal forms. In the first run (enthalpy of melting: DeltaH1), two endothermic peaks of alpha-form and beta-form were observed. However, in the second run (enthalpy of melting: DeltaH2), only the endothermic peak of the alpha-form was observed. From a strong correlation observed between the beta-form content in the mixture of alpha-form and beta-form and the enthalpy change, (DeltaH1-DeltaH2)/DeltaH2, beta-form content was expressed as a function of the enthalpy change. Using this relation, the stable beta-form content during the heat-treatment could be determined, and the maximum beta-form content was obtained when the heat-treatment was carried out at 50 degrees C. An inflection point existed in the time course of transformation of alpha-form to beta-form. It was assumed that almost all of alpha-form transformed to beta'-form at this point, and that subsequently only transformation from beta'-form to beta-form occurred. Based on this aspect, the transformation rate equations were derived as consecutive reaction. Experimental data coincided well with the theoretical curve. In conclusion, GM was transformed in the consecutive reaction, and 50 degrees C was the optimum heat-treatment temperature for transforming GM from the alpha-form to the stable beta-form.     

A fast and simple randomized parallel algorithm for the maximal independent set problem

A simple parallel randomized algorithm to find a maximal independent set in a graph G = (V, E) on n vertices is presented. Its expected running time on a concurrent-read concurrent-write PRAM with O(|E|d_max) processors is O(log n), where d_max denotes the maximum degree. On an exclusive-read exclusive-write PRAM with O(|E|) processors the algorithm runs in O(log²n). Previously, an O(log⁴n) deterministic algorithm was given by Karp and Wigderson for the EREW-PRAM model. This was recently (independently of our work) improved to O(log²n) by M. Luby. In both cases randomized algorithms depending on pairwise independent choices were turned into deterministic algorithms. We comment on how randomized combinatorial algorithms whose analysis only depends on d-wise rather than fully independent random choices (for some constant d) can be converted into deterministic algorithms. We apply a technique due to A. Joffe (1974) and obtain deterministic construction in fast parallel time of various combinatorial objects whose existence follows from probabilistic arguments.     

A decidualized endometrial cyst in a pregnant woman: a case observed with a steady-state free precession imaging sequence

Decidual changes of the ectopic endometrial stroma during pregnancy are well known among pathologists and obstetricians. However, they appear very similar to endometrial cysts with malignant transformation when imaged. Balanced fast field echo (BFFE) is a steady-state free precession imaging sequence and its contrast is decided by the T1/T2 ratio. The authors report a case of a decidualized endometrial cyst in which mural nodules were isointense with the nomotopic decidualized endometrium on T1- and T2-weighted images and BFFE. Isointensity with the nomotopic endometrium is an MR characteristic that can differentiate a decidualized endometrial cyst from malignant transformation. BFFE is a good alternative sequence during pregnancy because of its shorter acquisition time and lower radiofrequency absorption.     

Nobiletin: a citrus flavonoid displaying potent physiological activity

Nobiletin [systematic name: 2‐(3,4‐dimethoxyphenyl)‐5,6,7,8‐tetramethoxy‐4H‐chromen‐4‐one; C₂₁H₂₂O₈] is a flavonoid found in citrus peels, and has been reported to show a wide range of physiological properties, including anti‐inflammatory, anticancer and antidementia activities. We have solved the crystal structure of nobiletin, which revealed that the chromene and arene rings of its flavone moiety, as well as the two methoxy groups bound to its arene ring, were coplanar. In contrast, the C atoms of the four methoxy groups bound to the chromene ring are out of the plane, making the molecule conformationally chiral. A comparison of the crystal structures of nobiletin revealed that it could adopt a variety of different conformations through rotation of the covalent bond between the chromene and arene rings, and the orientations of methoxy groups bound to the chromene ring.     

Harmonic functions on planar and almost planar graphs and manifolds,via circle packings

The circle packing theorem is used to show that on any bounded valence transient planar graph there exists a non constant, harmonic, bounded, Dirichlet function. If is a bounded circle packing in whose contacts graph is a bounded valence triangulation of a disk, then, with probability , the simple random walk on converges to a limit point. Moreover, in this situation any continuous function on the limit set of extends to a continuous harmonic function on the closure of the contacts graph of ; that is, this Dirichlet problem is solvable. We define the notions of almost planar graphs and manifolds, and show that under the assumptions of transience and bounded local geometry these possess non constant, harmonic, bounded, Dirichlet functions. Let us stress that an almost planar graph is not necessarily roughly isometric to a planar graph. Oblatum 4-I-1995 & 23-IV-1996     

Expanders are not hyperbolic

We bound from above the number of vertices of a graph in terms of the Cheeger constant and the δ-hyperbolicity of the graph. As a corollary we get that expanders are not uniformly hyperbolic.     

Breakage mechanics—Part II: Modelling granular materials

The compression of granular materials has been traditionally modelled with the limitations of classical elasto-plasticity. The energy was implicitly assumed to dissipate from the frictional interaction of particles. However, the fact that brittle granular materials crush suggests that energy must also be dissipated from the fracturing of the grains, as in fracture mechanics. The concept of breakage as a thermomechanical internal variable was introduced in Part I [Einav, I., 2006. Breakage mechanics—Part I: theory. J. Mech. Phys. Solids 00,000-000] to describe the fracturing mechanisms. The theory allows to treat ideal theoretical materials that undergo dissipation purely from breakage with no other mechanism allowed for the energy consumption. However, as accounted for in elasto-plasticity, dissipation must also occur from the frictional rearrangement of grains. The combination of the two dissipative mechanisms of breakage and plasticity must therefore be investigated, as we do in this paper. Those two mechanisms are generally coupled, in the sense that one inevitably appears when the other develops. Plastic dissipation emerges as a by-product of breakage dissipation because after grains crush, local rearrangement must occur. This scenario may be termed an ‘active breakage mechanism’, and typifies compression deformations. In shear the plastic dissipation is dominant but breakage appears inevitably from grains abrasion. This scenario may be called a ‘passive breakage mechanism’. Based on the coupling assumption, models are developed for granular materials. In particular, we show that in compression isotropic hardening of sands may appear without involving plastic strains, i.e., independent of frictional dissipation. This interpretation of hardening is different from the one used in classical critical state soil mechanics. However, frictional dissipation leads to plastic straining that are necessary for the models to be predictive in unloading.     

Stereoselective Access to Fully Substituted Aldehyde-Derived Silyl Enol Ethers by Iridium-Catalyzed Alkene Isomerization

An in situ generated cationic Ir-catalyst isomerizes simple allylic silyl ethers into valuable, fully substituted aldehyde-derived silyl enol ethers. Importantly, by judicious choice of substrate, either of the two possible stereoisomers of a given enolate derivative is accessible with complete stereoselectivity. One-pot isomerization-aldol and isomerization-allylation processes illustrate the synthetic utility of this method.