Synthesis and carbonic anhydrase I, II, IX and XII inhibitory activity of sulfamates incorporating piperazinyl-ureido moieties

A series of sulfamates were synthesized using as lead compound SLC-0111, a sulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitor in Phase I clinical trials. The new derivatives incorporated ureido moieties as spacers between the benzene sulfamate fragment which binds the zinc ion from the active site, and the tail of the inhibitor, but the urea moieties were part of a substituted piperazine ring system. The derivatives (and some of their phenol precursors) were tested for the inhibition of the cytosolic, hCA I and II (off target isoforms) and the trans-membrane, tumor-associated hCA IX and XII enzymes (anticancer drug targets). Generally hCA I was not effectively inhibited, whereas many low nanomolar inhibitors were evidenced against hCA II (KIs in the range of 1.0–94.4 nM), IX (KIs in the range of 0.91–36.9 nM), and XII (KIs in the range of 1.0–84.5 nM). The best substitution fragments at the piperazine ring included the following moieties: 3-methylphenyl, 2,3-dimethylphenyl, 4-methoxyphenyl, 6-arylpyrimidine-2-yl

Synthesis of Sulfonamides Incorporating Piperidinyl-Hydrazidoureido and Piperidinyl-Hydrazidothioureido Moieties and Their Carbonic Anhydrase I, II, IX and XII Inhibitory Activity

Here we report a small library of hydrazinocarbonyl-ureido and thioureido benzenesulfonamide derivatives, designed and synthesized as potent and selective human carbonic anhydrase inhibitors (hCAIs). The synthesized compounds were evaluated against isoforms hCA I, II, IX and XII using acetazolamide (AAZ) as standard inhibitor. Several urea and thiourea derivatives showed inhibitory activity at low nanomolar levels with selectivity against the cytosolic hCA II isoform, as well as the transmembrane, tumor-associated enzymes hCA IX and XII. The thiourea derivatives showed enhanced potency as compared to urea analogues. Additionally, eight compounds 5g, 5m, 5o, 5q, 6l, 6j, 6o and 6u were selected for docking analysis on isoform I, II, IX, XII to illustrate the potential interaction with the enzyme to better understand the activity against the different isoforms

Investigation on Hydrazonobenzenesulfonamides as Human Carbonic Anhydrase I, II, IX and XII Inhibitors

A small series of hydrazonobenzenesulfonamides was designed, synthesized and studied for their human carbonic anhydrase (hCA) inhibitory activity. The synthesized compounds were evaluated against hCA I, II, IX and XII isoforms using acetazolamide (AAZ) as the standard inhibitor. Various hydrazonosulfonamide derivatives showed inhibitory activity at low nanomolar levels with selectivity against the cytosolic hCA II isoform, as well as the transmembrane, tumor-associated enzymes hCA IX and XII. The most potent and selective hydrazones 8, 9, 10, 11, 19 and 24 were docked into isoforms I, II, IX and XII to better understand their activity and selectivity for the different CA isoforms

Constraints on the magnetic field in the inter-cluster bridge A399-A401

Galaxy cluster mergers are natural consequences of the structure formation in the Universe. Such events involve a large amount of energy ($\sim 10^{63}$ erg) dissipated during the process. Part of this energy can be channelled in particle acceleration and magnetic field amplification, enhancing non-thermal emission of the intra- and inter-cluster environment. Recently, low-frequency observations have detected a bridge of diffuse synchrotron emission connecting two merging galaxy clusters, Abell 399 and Abell 401. Such a result provides clear observational evidence of relativistic particles and magnetic fields in-between clusters. In this work, we have used LOw Frequency ARray (LOFAR) observations at 144 MHz to study for the first time the polarized emission in the A399-A401 bridge region. No polarized emission was detected from the bridge region. Assuming a model where polarization is generated by multiple shocks, depolarization can be due to Faraday dispersion in the foreground medium with respect to the shocks. We constrained its Faraday dispersion to be greater than 0.10 rad m$^{-2}$ at 95% confidence level, which corresponds to an average magnetic field of the bridge region greater than 0.46 nG (or 0.41 nG if we include regions of the Faraday spectrum that are contaminated by Galactic emission). This result is largely consistent with the predictions from numerical simulations for Mpc regions where the gas density is $\sim 300$ times larger than the mean gas density.Comment: 12 pages, 13 figures; accepted in A&

Complete Exact Solution of Diffusion-Limited Coalescence, A + A -> A

Some models of diffusion-limited reaction processes in one dimension lend themselves to exact analysis. The known approaches yield exact expressions for a limited number of quantities of interest, such as the particle concentration, or the distribution of distances between nearest particles. However, a full characterization of a particle system is only provided by the infinite hierarchy of multiple-point density correlation functions. We derive an exact description of the full hierarchy of correlation functions for the diffusion-limited irreversible coalescence process A + A -> A.Comment: 4 pages, 2 figures (postscript). Typeset with Revte

Halogenated triazinediones behave as antagonists of PKR1: in vitro and in vivo pharmacological characterization

Different prokineticin receptor antagonists, based on the triazinedione scaffold, were synthesized by a new efficient method. Here we demonstrated that 5-benzyltriazinedionessubstituted in position para of the benzyl group with halogens provide compounds endowed with interesting selectivity for the Prokineticin receptor 1 (PKR1). BRET technology indicates that such substitutionresults in increased affinity for thePKR1.The affinity for PKR2, always in M range, was never significantly affected by the para-halogen-benzyl pharmacophores. The analog bearing a para-bromobenzyl pharmacophore (PC-25) displayed the highest affinity for PKR1 (~18 times higher than the reference PC-1 that bears apara-ethyl benzyl group) and the highest selectivity (~300 times). The other halogen substitutedanalogs (PC-7, PC-18 and PC-35), showed selectivity for PKR1 more than 100 times higher than for PKR2. Using transgenic mice lacking one of the two PKRs we demonstrated that all these compounds were able to abolish the Bv8-induced hyperalgesia in mice still expressing the PKR1 at doses lower than those necessary to abolish hyperalgesia in mice expressing only the PKR2. The dose ratio reflected the in- vitro evaluated receptor selectivity

A radio bubble shredded by gas sloshing?

We report on the detection of diffuse radio emission with peculiar morphology in the central region of the galaxy cluster Abell 2657. The most striking feature identified in our 144 MHz LOFAR image is a bifurcated radio arc that extends for a projected size of 150-200 kpc. From the analysis of XMM-Newton data, we find clear evidence of gas sloshing in the cluster and a possible dip in X-ray surface brightness between the two radio arcs which deserves confirmation. Interestingly, the synchrotron emission of the bifurcated radio arc is stretched along the sloshing spiral. We compare our observational results with numerical simulations of non-thermal components interacting with gas motions. We suggest that the detected emission may trace a radio bubble shredded by gas sloshing, where relativistic electrons and magnetic fields are expected to be stretched and stirred as a consequence of tangential flows induced by the spiralling gas motion. Lastly, we report on the presence of two thin (6-7 kpc in width) and parallel strands of radio emission embedded in the outer arc that are morphologically similar to the emerging population of non-thermal filaments observed in galaxy clusters, radio galaxies, and the Galactic centre. While this work further demonstrates the complex interplay between thermal and non-thermal components in the intracluster medium, follow-up observations in radio and X-rays are required to firmly determine the origin of the features observed in Abell 2657.Comment: 12 pages, 9 figures, 1 table. Accepted for publication in MNRA

Correlation Functions for Diffusion-Limited Annihilation, A + A -> 0

The full hierarchy of multiple-point correlation functions for diffusion-limited annihilation, A + A -> 0, is obtained analytically and explicitly, following the method of intervals. In the long time asymptotic limit, the correlation functions of annihilation are identical to those of coalescence, A + A -> A, despite differences between the two models in other statistical measures, such as the interparticle distribution function

A Method of Intervals for the Study of Diffusion-Limited Annihilation, A + A --> 0

We introduce a method of intervals for the analysis of diffusion-limited annihilation, A+A -> 0, on the line. The method leads to manageable diffusion equations whose interpretation is intuitively clear. As an example, we treat the following cases: (a) annihilation in the infinite line and in infinite (discrete) chains; (b) annihilation with input of single particles, adjacent particle pairs, and particle pairs separated by a given distance; (c) annihilation, A+A -> 0, along with the birth reaction A -> 3A, on finite rings, with and without diffusion.Comment: RevTeX, 13 pages, 4 figures, 1 table. References Added, and some other minor changes, to conform with final for

Novel non-equilibrium critical behavior in unidirectionally coupled stochastic processes

Phase transitions from an active into an absorbing, inactive state are generically described by the critical exponents of directed percolation (DP), with upper critical dimension d_c = 4. In the framework of single-species reaction-diffusion systems, this universality class is realized by the combined processes A -> A + A, A + A -> A, and A -> \emptyset. We study a hierarchy of such DP processes for particle species A, B,..., unidirectionally coupled via the reactions A -> B, ... (with rates \mu_{AB}, ...). When the DP critical points at all levels coincide, multicritical behavior emerges, with density exponents \beta_i which are markedly reduced at each hierarchy level i >= 2. This scenario can be understood on the basis of the mean-field rate equations, which yield \beta_i = 1/2^{i-1} at the multicritical point. We then include fluctuations by using field-theoretic renormalization group techniques in d = 4-\epsilon dimensions. In the active phase, we calculate the fluctuation correction to the density exponent for the second hierarchy level, \beta_2 = 1/2 - \epsilon/8 + O(\epsilon^2). Monte Carlo simulations are then employed to determine the values for the new scaling exponents in dimensions d<= 3, including the critical initial slip exponent. Our theory is connected to certain classes of growth processes and to certain cellular automata, as well as to unidirectionally coupled pair annihilation processes. We also discuss some technical and conceptual problems of the loop expansion and their possible interpretation.Comment: 29 pages, 19 figures, revtex, 2 columns, revised Jan 1995: minor changes and additions; accepted for publication in Phys. Rev.