Diketopiperazine-Based,Flexible Tadalafil Analogues: Synthesis,Crystal Structures and Biological Activity Profile

Phosphodiesterase 5 (PDE5) is one of the most extensively studied phosphodiesterases that is highly specific for cyclic-GMP hydrolysis. PDE5 became a target for drug development based on its efficacy for treatment of erectile dysfunction. In the present study, we synthesized four novel analogues of the phosphodiesterase type 5 (PDE5) inhibitor—tadalafil, which differs in (i) ligand flexibility (rigid structure of tadalafil vs. conformational flexibility of newly synthesized compounds), (ii) stereochemistry associated with applied amino acid building blocks, and (iii) substitution with bromine atom in the piperonyl moiety. For both the intermediate and final compounds as well as for the parent molecule, we have established the crystal structures and performed a detailed analysis of their structural features. The initial screening of the cytotoxic effect on 16 different human cancer and non-cancer derived cell lines revealed that in most cases, the parent compound exhibited a stronger cytotoxic effect than new derivatives, except for two cell lines: HEK 293T (derived from a normal embryonic kidney, that expresses a mutant version of SV40 large T antigen) and MCF7 (breast adenocarcinoma). Two independent studies on the inhibition of PDE5 activity, based on both pure enzyme assay and modulation of the release of nitric oxide from platelets under the influence of tadalafil and its analogues revealed that, unlike a reference compound that showed strong PDE5 inhibitory activity, the newly obtained compounds did not have a noticeable effect on PDE5 activity in the range of concentrations tested. Finally, we performed an investigation of the toxicological effect of synthesized compounds on Caenorhabditis elegans in the highest applied concentration of 6a,b and 7a,b (160 μM) and did not find any effect that would suggest disturbance to the life cycle of Caenorhabditis elegans. The lack of toxicity observed in Caenorhabditis elegans and enhanced, strengthened selectivity and activity toward the MCF7 cell line made 7a,b good leading structures for further structure activity optimization and makes 7a,b a reasonable starting point for the search of new, selective cytotoxic agents.     

Influence of Farming System and Forecrops of Spring Wheat on Protein Content in the Grain and the Physicochemical Properties of Unsonicated and Sonicated Gluten

The potential for enhancing the spring wheat protein content by different cultivation strategies was explored. The influence of ultrasound on the surface and rheological properties of wheat-gluten was also studied. Spring wheat was cultivated over the period of 2018–2020 using two farming systems (conventional and organic) and five forecrops (sugar beet, spring barley, red clover, winter wheat, or oat). The obtained gluten was sonicated using the ultrasonic scrubber. For all organically grown wheat, the protein content was higher than for the conventional one. There was no correlation between the rheological properties of gluten and the protein content in the grain. Gluten derived from organically grown wheat was more elastic than those derived from the conventional one. Sonication enhanced the elasticity of gluten. The sonication effect was influenced by the forecrops. The most elastic gluten after sonication was found for organic barley and sugar beet. The lowest values of tan (delta) were noted for conventional wheat and conventional oat. Cultivation in the monoculture gave gluten with a smaller susceptibility to increase elasticity after sonic treatment. Sonication promoted the cross-linking of protein molecules and induced a more hydrophobic character, which was confirmed by an increment in contact angles (CAs). Most of the organically grown wheat samples showed a lower CA than the conventional ones, which indicated a less hydrophobic character. The gluten surface became rougher with the sonication, regardless of the farming system and applied forecrops. Sonication treatment of gluten proteins rearranged the intermolecular linkages, especially disulfide and hydrophobic bonds, leading to changes in their surface morphology.     

Palladium catalysed regio- and stereoselective synthesis of (E)-4-aryl-1,3-bis(trimethylsilyl)but-3-en-1-ynes

A practical and general synthetic approach to a series of 4-aryl-but-3-en-1-ynes is described. In the presence of palladium complexes a variety of aryl bromides (or iodides) undergo coupling with two equivalents of trimethylsilylacetylene with the formation of (E)-4-aryl-1,3-bis(trimethylsilyl)but-3-en-1-ynes. The protocol is simple, efficient, and affords synthesis of regio- and stereoselectively target products in good to high yields.     

Speeds of sound and isentropic compressibilities of (2-ethoxyethanol + ethylene glycol, diethylene glycol, triethylene glycol, and tetraethylene glycol) binary mixtures at 298.15 K

The speed of sound (u) has been obtained at a frequency of 8.3 MHz in {CH₃CH₂OCH₂CH₂OH + HOCH₂CH₂(OCH₂CH₂)_nOH}for n = 0, 1, 2, and 3 over the whole composition range of studied binary liquid mixtures, at T = 298.15 K. The speed of sound values were combined with those of our previous results for densities and viscosities to obtain isentropic compressibility (κ_s), free volume (V_f), and intermolecular free length (L_f). From all these data excess isentropic compressibility (κ_s^E), excess free volume (V_f^E) and excess intermolecular free length (L_f^E) as well as the deviations of the speed of sound (Δu) were obtained. The results are interpreted in terms of molecular interactions occurring in the solutions.     

On the interaction between gold and copper in mercury

On the base of cyclic voltammetry, chronoamperometry and potentiometry experiments with the use of the hanging mercury drop electrodes, there was found that a solid AuCu compound is formed in the complex Au-Cu amalgam. The stability of AuCu is controlled by its solubility product, which is equal (7.1±1.5)·10^–6 M ² at 298 K. The temperature dependence of the solubility product allowed to determine H _AuCu of formation in mercury. This value is compared with H _AuCu of the reaction in the binary system. On the basis of theBorn-Haber cycle one may conclude that the AuCu formed in mercury phase should have the same structure as in the binary alloy. Some thermodynamic aspects of reactions in the Au-Cu-Ga amalgam are discussed. The solubility of copper in mercury was experimentally confirmed and is equal (1.1±0.1) · 10^–2at.%.

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Über die Wechselwirkung zwischen Gold und Kupfer in Quecksilber

Zusammenfassung Mit Hilfe von voltammetrischen, chronoamperometrischen und potentiometrischen Experimenten mit der hängenden Quecksilbertropfelektrode wurde eine feste AuCu-Verbindung in Au-Cu-Amalgam gefunden. Die Beständigkeit der Verbindung AuCu wird durch das Löslichkeitsprodukt bestimmt, das gleich (7,1 ± 1,5) · 10^–6 M ² bei 298 K ist. Die Temperaturabhängigkeit des Löslichkeitsproduktes erlaubt die Bestimmung der Bildungswärme H _AuCu der Verbindung in Quecksilber. Dieser Wert wird mit der Bildungswärme H _AuCu im binären System verglichen. Auf der Basis desBorn-Haber-Kreisprozesses kann man schließen, daß das in Quecksilber gebildete AuCu dieselbe Struktur wie im binären System hat. Verschiedene thermodynamische Aspekte der Reaktionen in Au-Cu-Ga-Amalgam werden diskutiert. Die Löslichkeit von Kupfer in Quecksilber wurde experimentell bestätigt und beträgt (1,1 ± 0,1) · 10^–2 at.%.

     

Improving the Accuracy of the Fast Inverse Square Root by Modifying Newton–Raphson Corrections

Direct computation of functions using low-complexity algorithms can be applied both for hardware constraints and in systems where storage capacity is a challenge for processing a large volume of data. We present improved algorithms for fast calculation of the inverse square root function for single-precision and double-precision floating-point numbers. Higher precision is also discussed. Our approach consists in minimizing maximal errors by finding optimal magic constants and modifying the Newton–Raphson coefficients. The obtained algorithms are much more accurate than the original fast inverse square root algorithm and have similar very low computational costs.     

Studies on the catalysis of the reaction of organotin phenoxides with bis(2,2,2‐trichloroethyl) azodicarboxylate by lithium perchlorate

Organotin phenoxides, which are distinctly more active than the corresponding phenols, react at room temperature with bis(2,2,2‐trichloroethyl) azodicarboxylate to produce para‐substituted phenolic hydrazides in high yields. Copyright © 2004 John Wiley & Sons, Ltd.