Diferratricarbaboranes of the subcloso-[(eta5-C5H5)2Fe2C3B8H11] type, the first representatives of the 13-vertex dimetallatricarbaborane series

Treatment of the [2-Cp-9-tBuNH-closo-2,1,7,9-FeC(3)B(8)H(10)] (1) ferratricarbollide (Cp = eta(5)-C(5)H(5) (-)) with Na(+) C(10)H(8) (-) in 1,2-dimethoxyethane (DME) at room temperature produced an air-sensitive transient anion with a tentatively identified nido-[tBuNH-CpFeC(3)B(8)H(10)](2-) constitution. In-situ reaction of this low-stability ion with [CpFe(CO)(2)I] or [CpFe(CO)(2)](2) generated three violet diferratricarbaboranes identified as paramagnetic subcloso complexes [4,5-Cp(2-)-4,5,1,6,7-Fe(2)C(3)B(8)H(11)] (2; yield 2 %), [4,5-Cp(2-)-4,5,1,7,12-Fe(2)C(3)B(8)H(11)] (3; yield 2 %), and [7-tBuNH-4,5-Cp(2-)-4,5,1,7,12-Fe(2)C(3)B(8)H(10)] (4; yield 14 %). These first representatives of the 13-vertex dimetallatricarbaborane family were characterized by EPR and IR spectroscopy, and mass spectrometry, and their structures were determined by X-ray diffraction analysis.     

The discovery of Kv1.5 blockers as a case study for the application of virtual screening approaches

Different virtual screening techniques are available as alternatives to high throughput screening. These different techniques have been rarely used together on the same target. We had the opportunity to do so in order to discover novel blockers of the voltage-dependent potassium channel Kv1.5, a potential target for the treatment of atrial fibrillation. Our corporate database was searched, using a protein-based pharmacophore, derived from a homology model, as query. As a result, 244 molecules were screened in vitro, 19 of them (7.8%) were found to be active. Five of them, belonging to five different chemical classes, exhibited IC50 values under 10 microM. The performance of this structure-based virtual screening protocol has been compared with those of similarity and ligand-based pharmacophore searches. The analysis of the results supports the conventional wisdom of using as many virtual screening techniques as possible in order to maximize the chance of finding as many chemotypes as possible.     

Second‐Generation Inhibitors for the Metalloprotease Neprilysin Based on Bicyclic Heteroaromatic Scaffolds: Synthesis,Biological Activity,and X‐Ray Crystal‐Structure Analysis

A new class of nonpeptidic inhibitors of the Zn^II‐dependent metalloprotease neprilysin with IC₅₀ values in the nanomolar activity range (0.034–0.30 μM ) were developed based on structure‐based de novo design (Figs. 1 and 2). The inhibitors feature benzimidazole and imidazo[4,5‐c]pyridine moieties as central scaffolds to undergo H‐bonding to Asn542 and Arg717 and to engage in favorable π‐π stacking interactions with the imidazole ring of His711. The platform is decorated with a thiol vector to coordinate to the Zn^II ion and an aryl residue to occupy the hydrophobic S1′ pocket, but lack a substituent for binding in the S2′ pocket, which remains closed by the side chains of Phe106 and Arg110 when not occupied. The enantioselective syntheses of the active compounds (+)‐ 1 , (+)‐ 2 , (+)‐ 25 , and (+)‐ 26 were accomplished using Evans auxiliaries (Schemes 2, 4, and 5). The inhibitors (+)‐ 2 and (+)‐ 26 with an imidazo[4,5‐c]pyridine core are ca. 8 times more active than those with a benzimidazole core ((+)‐ 1 and (+)‐ 25 ) (Table 1). The predicted binding mode was established by X‐ray analysis of the complex of neprilysin with (+)‐ 2 at 2.25‐Å resolution (Fig. 4 and Table 2). The ligand coordinates with its sulfanyl residue to the Zn^II ion, and the benzyl residue occupies the S1′ pocket. The 1H‐imidazole moiety of the central scaffold forms the required H‐bonds to the side chains of Asn542 and Arg717. The heterobicyclic platform additionally undergoes π‐π stacking with the side chain of His711 as well as edge‐to‐face‐type interactions with the side chain of Trp693. According to the X‐ray analysis, the substantial advantage in biological activity of the imidazo‐pyridine inhibitors over the benzimidazole ligands arises from favorable interactions of the pyridine N‐atom in the former with the side chain of Arg102. Unexpectedly, replacement of the phenyl group pointing into the deep S1′ pocket by a biphenyl group does not enhance the binding affinity for this class of inhibitors.     

Beiträge zur qualitativen „Test Tube“-Papierchromatographie

Zusammenfassung Bei der Trennung und Bestimmung verschiedener reiner Aminosäuren wurde die in vieler Hinsicht einfachere und raschere Test Tube-Methodik näher studiert. Zum Lösen der Aminosäuren erwies sich Ameisensäure als besonders günstig. Bezüglich des Trennungseffektes haben sich als Eintauchmittel besonders eine Mischung von n-Propanol-Wasser und bestimmte ternäre Gemische von tert. Butanol-Methyläthylketon-Wasser und tert. Butanol-Methanol-Wasser bewährt. Außerdem wurde festgestellt, daß die Test Tube-Papierchromatographie besonders auch bei höheren Temperaturen verwendbar ist und hier bessere und raschere Trennungseffekte erzielt werden können. Die Fehlerquellen bei der Bestimmung derR _f Werte wurden eingehend geprüft und dieR _f Werte von 19 Aminosäuren bei verschiedenen Bedingungen in Tabellen angegeben.

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Summary A closer study of the Test Tube Method, which is simpler and faster, was made in the separation and determination of various amino acids. Formic acid was found to be especially good for dissolving the amino acids. With respect to the separation effect, it was found that a mixture of n-propanolwater and certain ternary mixtures of tertiary butanol -methylethylketone-water and tertiary butanol-methanol-water are good as immersion agents. It was also shown that the Test Tube paper chromatography is also applicable at higher temperatures and gives better and more rapid separation effects. The sources of error in the determination of theR _f values were investigated closely and a table is included showing theR _f values of 19 amino acids under various conditions.

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Résumé On a approfondi l'étude de la «technique du tube à essais» dont l'emploi pour la séparation et le dosage de différents amino-acides purs est des plus simples et des plus rapides à de multiples points de vue. Il est apparu que l'acide formique était un solvant particulièrement approprié pour les aminoacides. En ce qui concerne l'effet de séparation, on a obtenu d'excellents résultats par immersion dans un mélange de propanol normal et d'eau ou dans des mélanges ternaires définis de butanol tertiaire, de méthyléthylcétone et d'eau ou de butanol tertiaire, de méthanol et d'eau. On a, en outre, établi que la chromatographie sur papier par la méthode du «tube à essais» est également utilisable lorsqu'on élève la température et qu'elle permet alors d'obtenir des effets de séparation meilleurs et plus rapides. Les sources d'erreurs de la détermination des valeurs deR _f ont été étudiées en détail; un tableau fournit les valeurs deR _f relatives à 19 aminoacides dans des conditions diverses.