A Compound Poisson Perspective of Ewens–Pitman Sampling Model

The Ewens–Pitman sampling model (EP-SM) is a distribution for random partitions of the set {1,…,n}, with n∈N, which is indexed by real parameters α and θ such that either α∈[0,1) and θ>−α, or α<0 and θ=−mα for some m∈N. For α=0, the EP-SM is reduced to the Ewens sampling model (E-SM), which admits a well-known compound Poisson perspective in terms of the log-series compound Poisson sampling model (LS-CPSM). In this paper, we consider a generalisation of the LS-CPSM, referred to as the negative Binomial compound Poisson sampling model (NB-CPSM), and we show that it leads to an extension of the compound Poisson perspective of the E-SM to the more general EP-SM for either α∈(0,1), or α<0. The interplay between the NB-CPSM and the EP-SM is then applied to the study of the large n asymptotic behaviour of the number of blocks in the corresponding random partitions—leading to a new proof of Pitman’s α diversity. We discuss the proposed results and conjecture that analogous compound Poisson representations may hold for the class of α-stable Poisson–Kingman sampling models—of which the EP-SM is a noteworthy special case.

Synthesis and Enantioselective Pharmacokinetic/Pharmacodynamic Analysis of New CNS-Active Sulfamoylphenyl Carbamate Derivatives

We recently reported a new class of carbamate derivatives as anticonvulsants. Among these, 3-methylpentyl(4-sulfamoylphenyl)carbamate (MSPC) stood out as the most potent compound with ED50 values of 13 mg/kg (i.p.) and 28 mg/kg (p.o.) in the rat maximal electroshock test (MES). 3-Methylpropyl(4-sulfamoylphenyl)carbamate (MBPC), reported and characterized here, is an MSPC analogous compound with two less aliphatic carbon atoms in its structure. As both MSPC and MBPC are chiral compounds, here, we studied the carbonic anhydrase inhibitory and anticonvulsant action of both MBPC enantiomers in comparison to those of MSPC as well as their pharmacokinetic properties. Racemic-MBPC and its enantiomers showed anticonvulsant activity in the rat maximal electroshock (MES) test with ED50 values in the range of 19–39 mg/kg. (R)-MBPC had a 65% higher clearance than its enantiomer and, consequently, a lower plasma exposure (AUC) than (S)-MSBC and racemic-MSBC. Nevertheless, (S)-MBPC had a slightly better brain permeability than (R)-MBPC with a brain-to-plasma (AUC) ratio of 1.32 (S-enantiomer), 1.49 (racemate), and 1.27 (R-enantiomer). This may contribute to its better anticonvulsant-ED50 value. The clearance of MBPC enantiomers was more enantioselective than the brain permeability and MES-ED50 values, suggesting that their anticonvulsant activity might be due to multiple mechanisms of action.

Reduced 3,4′-bipyrazoles carrying thiophene and thiazole substituents: structures of two intermediates and two products

Cycloaddition reactions between 3-(5-aryloxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)-1-(thiophen-2-yl)prop-2-en-1-ones and thiosemicarbazide leads to the formation of reduced 3,4′-bipyrazole-2-carbothioamides. Further cycloaddition of these intermediates with either diethyl acetylenedicarboxylate or 4-bromophenacyl bromide leads to reduced 3,4′-bipyrazoles carrying oxothiazole or thiazole substituents, respectively. The structures of two representative intermediates and two representative products established unambiguously the regiochemistry of the cycloaddition reactions. The molecules of 3′-methyl-5′-(2-methylphenoxy)-1′-phenyl-5-(thiophen-2-yl)-3,4-dihydro-1′H,2H-3,4′-bipyrazole-2-carbothioamide, C25H23N5OS2 (Ia), are linked by N—H...N hydrogen bonds to form simple C(8) chains. The analogous compound 5′-(2,4-dichlorophenoxy)-3′-methyl-1′-phenyl-5-(thiophen-2-yl)-3,4-dihydro-1′H,2H-3,4′-bipyrazole-2-carbothioamide hemihydrate crystallizes as a hemihydrate, C24H19Cl2N5OS2·0.5H2O (Ib), and the independent components are linked into a chain of spiro-fused R 4 4(20) rings by a combination of O—H...N and N—H...O hydrogen bonds. In the structure of ethyl (Z)-2-{2-[3′-methyl-1′-phenyl-5-(thiophen-2-yl)-5′-(2-methylphenoxy)-3,4-dihydro-1′H,2H-3,4′-bipyrazole-2-yl]-4-oxo-4,5-dihydrothiazol-5-ylidene}acetate, C31H27N5O4S2 (II), inversion-related pairs of molecules are linked by paired C—H...π(arene) hydrogen bonds to form cyclic centrosymmetric dimers, but there are no direction-specific intermolecular interactions in 4-(4-bromophenyl)-2-[5′-(2,4-dichlorophenoxy)-3′-methyl-1′-phenyl-5-(thiophen-2-yl)-3,4-dihydro-1′H,2H-3,4′-bipyrazole-2-yl]-4-thiazole, C32H22BrCl2N5OS2 (III). Comparisons are made with the structures of some related compounds.

Azologization and repurposing of a hetero-stilbene-based kinase inhibitor: towards the design of photoswitchable sirtuin inhibitors

The use of light as an external trigger to change ligand shape and as a result its bioactivity, allows the probing of pharmacologically relevant systems with spatiotemporal resolution. A hetero-stilbene lead resulting from the screening of a compound that was originally designed as kinase inhibitor served as a starting point for the design of photoswitchable sirtuin inhibitors. Because the original stilbenoid structure exerted unfavourable photochemical characteristics it was remodelled to its heteroarylic diazeno analogue. By this intramolecular azologization, the shape of the molecule was left unaltered, whereas the photoswitching ability was improved. As anticipated, the highly analogous compound showed similar activity in its thermodynamically stable stretched-out (E)-form. Irradiation of this isomer triggers isomerisation to the long-lived (Z)-configuration with a bent geometry causing a considerably shorter end‐to‐end distance. The resulting affinity shifts are intended to enable real‐time photomodulation of sirtuins in vitro.

Azologization of a hetero-stilbene based c-RAF kinase inhibitor: Towards the design of photoswitchable sirtuin inhibitors

The use of light as an external trigger to change ligand shape and as a result its bioactivity, allows the probing of pharmacologically relevant systems with spatiotemporal resolution. In this context, aromatic diazeno compounds are well suited for the design of photoswitchable ligands due to the long thermal relaxation half‐lives of the photoinduced Z configuration, and tunability of the absorption wavelength λ max. In search for sirtuin inhibitors, a hetero-stilbene lead resulting from the screening of a compound that was originally designed as kinase inhibitor, was remodelled to its diazeno analogue. By this azologization, the shape of the molecule was left unaltered whereas the photoswitching ability was improved. As anticipated, the highly analogous compound showed similar activity in its thermodynamically stable stretched-out E form. Irradiation of this isomer triggers isomerisation to the Z configuration with a bent geometry causing a considerably shorter end‐to‐end distance. The resulting affinity shifts are intended to enable real‐time photomodulation of sirtuins in vitro.

Enabling microbial syringol conversion through structure-guided protein engineering

Microbial conversion of aromatic compounds is an emerging and promising strategy for valorization of the plant biopolymer lignin. A critical and often rate-limiting reaction in aromatic catabolism isO-aryl-demethylation of the abundant aromatic methoxy groups in lignin to form diols, which enables subsequent oxidative aromatic ring-opening. Recently, a cytochrome P450 system, GcoAB, was discovered to demethylate guaiacol (2-methoxyphenol), which can be produced from coniferyl alcohol-derived lignin, to form catechol. However, native GcoAB has minimal ability to demethylate syringol (2,6-dimethoxyphenol), the analogous compound that can be produced from sinapyl alcohol-derived lignin. Despite the abundance of sinapyl alcohol-based lignin in plants, no pathway for syringol catabolism has been reported to date. Here we used structure-guided protein engineering to enable microbial syringol utilization with GcoAB. Specifically, a phenylalanine residue (GcoA-F169) interferes with the binding of syringol in the active site, and on mutation to smaller amino acids, efficient syringolO-demethylation is achieved. Crystallography indicates that syringol adopts a productive binding pose in the variant, which molecular dynamics simulations trace to the elimination of steric clash between the highly flexible side chain of GcoA-F169 and the additional methoxy group of syringol. Finally, we demonstrate in vivo syringol turnover inPseudomonas putidaKT2440 with the GcoA-F169A variant. Taken together, our findings highlight the significant potential and plasticity of cytochrome P450 aromaticO-demethylases in the biological conversion of lignin-derived aromatic compounds.

Red luminescence and ferromagnetism in europium oxynitridosilicates with a β-K2SO4 structure

LaSrSiO3N and LaBaSiO3N are the first examples of nitride-based alkaline earth orthosilicates with β-K2SO4 structure, and they show red-orange luminescence after activation with Eu2+. The analogous compound LaEuSiO3N is, in addition to a red phosphor material, a soft ferromagnet with a Curie temperature of 3 K.

Supramolecular architecture of PGM-arene-amino acid complexes

Arene complexes of Platinum Group Metals (PGM) show various biological effects and there are several promising anticancer drug candidates in this class of compounds. Synergism of biological activity is foreseen when anciliary ligands such as amino acid derivatives or other bioligands are incorporated into the complexes. A series of Ru(II), Os(II), Rh(III) and Ir(III) complexes were studied and interesting kinetic/equilibrium/structural properties could be revealed [1-3]. According to our latest results presented here the N-acetylcysteine complex of the [(η6-Ar)Ru]2+ core (Ar = p-cymene) is a dimer showing bridging thiolate and chloride cordination (Figure 1, a) while a monomeric complex was formed with [S, COO–,NH2] coordination for S-methyl-cysteine when the counter ion is nitrate (Figure 1, b). With methionine an analogous compound was formed (Figure 1, c). Supramolecular analysis of the complexes indicates competing steric/Coulombic/van der Waals interactions and hydrogen bonds. X-ray diffraction and spectroscopic analysis revealed the structure of the complexes both in solution and in the solid state and also support kinetic/equilibrium findings. Acknowledgement: The research was supported by the EU and co-financed by the European Social Fund under the project ENVIKUT (TÁMOP-4.2.2.A-11/1/KONV-2012-0043). The work was supported by the Hungarian Scientific Research Fund (OTKA K76142), too. P.B. thanks members of the EU COST Action CM1105 for motivating discussions. G.B. acknowledges the support of the Bolyai János Scholarship of the Hungarian Academy of Sciences.

Head-to-tail square-shaped cyclic hydrogen bonds leading to dimeric aggregates: 1,8-dibenzoyl-2,7-dihydroxynaphthalene and a comparison with its analogous benzoylnaphthalene

The title compound, C24H16O4, crystallized with two independent molecules in the asymmetric unit. Both carbonyl groups in these molecules form intramolecular O—H...O=C hydrogen bonds with neighbouring hydroxy groups, affording six-membered cyclic structures. In the crystal, dimeric aggregates arise from two intermolecular O—H...O=C hydrogen bonds between both independent molecules, forming head-to-tail square-shaped cyclic ...O...H...O...H... hydrogen bonds. These dimeric aggregates are connected into layers in thebcplane by intermolecular (naphthalene)C—H...O=C interactions. On the other hand, the analogous compound bearing methoxy groups at the 2- and 7-positions of the naphthalene ring, namely 1,8-dibenzoyl-2,7-dimethoxynaphthalene [Nakaemaet al.(2008).Acta Cryst.E64, o807], forms a three-dimensional molecular networkviaC—H...O=C and π–π interactions between the benzoyl groups. These results show that the intramolecular O—H...O=C hydrogen bonds in the title compound control the orientations of the benzoyl groups and thus promote the formation of the cyclic intermolecular O—H...O=C interactions involving the same donor and acceptor groups in pairs of molecules.