Regioselective Synthesis of 5- and 3-Hydroxy-N-Aryl-1H-Pyrazole-4-Carboxylates and Their Evaluation as Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase

In silico evaluation of various regioisomeric 5- and 3-hydroxy-substituted alkyl 1-aryl-1H-pyrazole-4-carboxylates and their acyclic precursors yielded promising results with respect to their binding in the active site of dihydroorotate dehydrogenase of Plasmodium falciparum (PfDHODH). Consequently, four ethyl 1-aryl-5-hydroxy-1H-pyrazole-4-carboxylates and their 3-hydroxy regioisomers were prepared by two-step syntheses via enaminone-type reagents or key intermediates. The synthesis of 5-hydroxy-1H-pyrazoles was carried out using the literature protocol comprising acid-catalyzed transamination of diethyl [(dimethylamino)methylene]malonate with arylhydrazines followed by base-catalyzed cyclization of the intermediate hydrazones. For the synthesis of isomeric methyl 1-aryl-3-hydroxy-1H-pyrazole-4-carboxylates, a novel two-step synthesis was developed. It comprises acylation of hydrazines with methyl malonyl chloride followed by cyclization of the hydrazines with tert-butoxy-bis(dimethylamino)methane. Testing the pyrazole derivatives for the inhibition of PfDHODH showed that 1-(naphthalene-2-yl)-5-hydroxy-1H-pyrazole-4-carboxylate and 1-(naphthalene-2-yl)-, 1-(2,4,6-trichlorophenyl)-, and 1-[4-(trifluoromethyl)phenyl]-3-hydroxy-1H-pyrazole-4-carboxylates (~30% inhibition) were slightly more potent than a known inhibitor, diethyl α-{[(1H-indazol-5-yl)amino]methylidene}malonate (19% inhibition).     

Cancer-Associated Mutations of the Adenosine A2A Receptor Have Diverse Influences on Ligand Binding and Receptor Functions

The adenosine A_2A receptor (A_2AAR) is a class A G-protein-coupled receptor (GPCR). It is an immune checkpoint in the tumor micro-environment and has become an emerging target for cancer treatment. In this study, we aimed to explore the effects of cancer-patient-derived A_2AAR mutations on ligand binding and receptor functions. The wild-type A_2AAR and 15 mutants identified by Genomic Data Commons (GDC) in human cancers were expressed in HEK293T cells. Firstly, we found that the binding affinity for agonist NECA was decreased in six mutants but increased for the V275A mutant. Mutations A165V and A265V decreased the binding affinity for antagonist ZM241385. Secondly, we found that the potency of NECA (EC₅₀) in an impedance-based cell-morphology assay was mostly correlated with the binding affinity for the different mutants. Moreover, S132L and H278N were found to shift the A_2AAR towards the inactive state. Importantly, we found that ZM241385 could not inhibit the activation of V275A and P285L stimulated by NECA. Taken together, the cancer-associated mutations of A_2AAR modulated ligand binding and receptor functions. This study provides fundamental insights into the structure–activity relationship of the A_2AAR and provides insights for A_2AAR-related personalized treatment in cancer.     

Chitosan nanostructures deposited from solutions in carbonic acid on a model substrate as resolved by AFM

Chitosan macromolecules can be dissolved in water saturated with CO₂ under high pressure, i.e. in carbonic acid. This unique biocompatible solvent with acidity regulated by the variation of applied CO₂ pressure is rather promising for biomedical applications. In this work the main features of deposition of chitosan structures on the model substrate from solutions in this media were examined. After deposition on the mica surface, the obtained structures have been successfully visualised by atomic force microscopy (AFM). It has been found out that they adsorb as rather peculiar elongated objects with an average length of about 70?nm. Such conformations are believed to appear due to amphiphilic nature of chitosan semiflexible chains in agreement with recent theoretical findings. The well-defined geometry of the elongated monodispersed structures allows them to demonstrate some elements of liquid crystalline-like ordering.     

Modelling of Drop Size Distribution of Rain from Rain Rate and Attenuation Measurements at Millimeter and Optical Wavelengths

This paper describes a technique for modelling of rain drop size distributions at Calcutta in terms of negative exponential function, from the measurements of rain rate and attenuation over a dual wavelength LOS link at millimeter and optical frequencies. The DSD model obtained is then used to determine the attenuation at 94 GHz, for comparison with experimentally obtained attenuation at 94 GHz. This is also compared with the attenuation calculated by considering other experimentally obtained DSD models. The best fit negative exponential distribution function (modified M-P model) is presented along with some other experimentally obtained and reference models.     

Buyer-seller exactness in the assignment game

In the assignment game framework, we try to identify those assignment matrices in which no entry can be increased without changing the core of the game. These games will be called buyer-seller exact games and satisfy the condition that each mixed-pair coalition attains the corresponding matrix entry in the core of the game. For a given assignment game, a unique buyer-seller exact assignment game with the same core is proved to exist. In order to identify this matrix and to provide a characterization of those assignment games which are buyer-seller exact in terms of the assignment matrix, attainable upper and lower core bounds for the mixed-pair coalitions are found. As a consequence, an open question posed in Quint (1991) regarding a canonical representation of a “45^o-lattice” by means of the core of an assignment game can now be answered. Received: March 2002/Revised version: January 2003 RID="*" ID="*"  Institutional support from research grants BEC 2002-00642 and SGR2001-0029 is gratefully acknowledged RID="**" ID="**"  The authors thank the referees for their comments     

Future Strategy for the New Millennium Wireless World

Wireless Personal Communications -     

Specific Interaction of Coproporphyrin I with Antibodies in Water and Reverse Micelles: Dimerization of Antibodies Affects Antigen Binding Site

The antigen-antibody interaction between coproporphyrin I and anti-coproporphyrin antibodies was studied by a fluorescence method in water and a reverse micellar system: n-octane/Aerosol OT. Coproporphyrin fluorescence was quenched, and coproporphyrin emission maximum was shifted to the long-wavelength region after binding to the antibodies or Fab-fragments. The mechanism of this quenching is static, most probably, by a tryptophan residue (or maybe lysine or methionine). Apparent dynamic quenching, in this case, arises from protein backbone motion. A special kind of antibody Fab-Fab dimerization was proposed.