Tetrahydroindoles as Multipurpose Screening Compounds and Novel Sirtuin Inhibitors

Indoles are privileged structures in medicinal and bioorganic chemistry that are particularly well suited to serve as platforms for diversity. Among many other therapeutic areas, the indole scaffold has been used to design aromatic compounds useful to interfere with enzymes engaged in the regulation of substrate acylation status, such as sirtuins. However, the planarity of the indole ring is not necessarily optimal for all target enzymes, especially when functionalization with aromatic side chains is required. Replacement of flat scaffolds by nonplanar molecular cores dominated by sp³ hybridization is a common strategy to avoid the disadvantages associated with poor solubility and high promiscuity, while covering less-well-explored areas of chemical space. Thus, we synthesized fragment-like tetrahydroindoles suitable for fragment-based drug discovery as well as a well-characterized small library intended as multipurpose screening compounds. For proof of principle, these compounds were screened against sirtuins 1–3, enzymes known to be addressable by indoles. We found that 2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamides are potent and selective SIRT2 inhibitors. Compound 16 t displayed an IC₅₀ value of 0.98 μm and could serve as exquisite starting point for hit-to-lead profiling.     

The Critical Role of Passive Permeability in Designing Successful Drugs

Passive permeability is a key property in drug disposition and delivery. It is critical for gastrointestinal absorption, brain penetration, renal reabsorption, defining clearance mechanisms and drug-drug interactions. Passive diffusion rate is translatable across tissues and animal species, while the extent of absorption is dependent on drug properties, as well as in vivo physiology/pathophysiology. Design principles have been developed to guide medicinal chemistry to enhance absorption, which combine the balance of aqueous solubility, permeability and the sometimes unfavorable compound characteristic demanded by the target. Permeability assays have been implemented that enable rapid development of structure-permeability relationships for absorption improvement. Future advances in assay development to reduce nonspecific binding and improve mass balance will enable more accurately measurement of passive permeability. Design principles that integrate potency, selectivity, passive permeability and other ADMET properties facilitate rapid advancement of successful drug candidates to patients.     

Zur härtung von diandiglycidylether mit anhydridmodifizierten phenolischen härtern und zu vergleichbaren in situ-reaktionen

The curing of diglycidyl ether of bisphenol A (DGEBA) with 2,6-dimethylol-p-cresol modified by hexahydrophthalic acid anhydride was investigated and compared with the analogous in situ curing of DGEBA, hexahydrophthalic acid anhydride and 2,6-dimethylol-p-cresol. The chemical reactions were investigated by means of titration and different spectroscopic and chromatographic methods. It was examined whether the less complicated and therefore cheaper in situ reaction delivers postcured products with equal or better properties. Furthermore, it was investigated whether the results are similar using technical phenolic hardeners.     

Proteine des Bienenhonigs

Zusammenfassung Die Isolierung der Saccharase (E.C. 3.2.1.20) aus den Proteinkonzentraten von Raps-, Tannen- und Zuckerfütterungshonig wird beschrieben. Die Abtrennung von anderen Enzymen, insbesondere von saurer Phosphatase gelingt durch hydrophobe Wechselwirkungschromatographie, von inerten Proteinen durch Gelfiltration. Im Zusammenhang damit wird das Verhalten des Enzyms bei der Chromatographie an Anionenaustauschern, an Hydroxylapatit und an immobilisiertem Weizenkeimlectin untersucht. Dabei ergab sich am Lectin-Gel eine Trennung in zwei multiple Formen.Die Saccharase aus allen drei Honigsorten verhielt sich einheitlich, woraus zu schließen ist, daß sie ausschließlich von der Biene stammt. Ihre Molekül masse wurde gelchromatographisch zu 57000 ermittelt.

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The proteins of honeyVIII. Honey sucrase, isolation, chromatographic behaviour and properties

Summary The isolation of the honey sucrase (E.C. 3.2.1.20) from rape- and fir-honey as well as from honey obtained after sugar feeding is described. The separation from other honey enzymes especially from acid phosphatase succeded by reversed phase chromatography. Separation of other, non-active proteins was accomplished by gel permeation chromatography. The behaviour of the honey sucrase upon chromatography on anion exchangers, on hydroxylapatite and wheat germ lectin was investigated. No differences were found between the sucrases of the three honeys.The molecular weight was determined at 57 000. By affinity chromatography with wheat germ lectin the enzyme could be separated into two multiple forms.

     

A survey on the occurrence of Fusarium mycotoxins in Bavarian cereals from the 1987 harvest

Summary Bavarian cereals and wheat flour from the 1987 harvest were analysed for nivalenol (NIV) and deoxynivalenol (DON) using high performance liquid chromatography (HPLC) and for T-2 toxin and zearalenone (ZEA) by enzyme-linked-immunosorbent as say (ELISA). The study included 190 field samples of wheat, barley, rye and oat with visibly damaged ears, 45 samples of wheat intended for feed production and two series of wheat flour (type 550) and whole wheat flour collected in October 1987 and June 1988. The field samples examined showed a high DON contamination of wheat (87%) with an average of 3.96 mg/kg and a maximum of 43.8 mg/kg. Mean levels between 0.33 mg/kg and 0.27 mg/kg DON could be detected in barley, rye and oat. Of the wheat samples, 58% contained ZEA with a maximum of 1.560 mg/kg. The highest levels of ZEA were detected in samples which also showed high concentrations of DON. The NIV and T-2 toxin levels were comparatively low. Thirty percent of the samples showed NIV concentrations between 0.04 mg/kg and 0.29 mg/kg and 38% contained between 0.005 and 0.60 mg/kg of T-2. In the wheat samples for feed production, only DON was detected with an average of 0.190 mg/kg and a maximum of 0.75 mg/kg. The highest DON levels (0.58 mg/kg) from October 1987 were found in the wheat flour samples which were lower than the highest DON concentration (3.24 mg/kg) detected in the samples collected during June 1988. This fact was probably due to a substantial amount of non-contaminated wheat from 1986. The toxin concentrations in the whole wheat flour were not higher than in the type 550 flour. The regional distribution of the mean DON concentrations showed the highest levels in Middle and Lower-Franconia.

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Vorkommen von Fusarium Mykotoxinen in bayerischem Getreide der Ernte 1987

Zusammenfassung Cerealien und Weizenmehle der bayerischen Ernte 1987 wurden mittels hochauflösender Flüssigchromatographie (HPLC) auf Nivalenol (NIV) und Deoxynivalenol (DON) Bowie mit Enzymimmunoassay auf T-2 Toxin und Zearalenon (ZEA) analysiert. Die Untersuchungen umfaßten 190 Feldproben von Weizen, Gerste, Roggen und Hafer, die alle optisch erkennbaren Fusarienbefall aufwiesen, 45 Futterweizenproben Bowie zwei Probenserien von Weizenmehlen der Type 550 und Vollkornweizenmehlen, die im October 1987 und im Juni 1988 gezogenwurden. — Die Untersuchungen der Feldproben ergaben eine hohe DON-Kontamination des Weizens (87%) mit einem durchschnittlichen Gehalt von 3,96 mg/kg und einem Maximalgehalt von 43,8 mg/kg. In Gerste, Roggen und Hafer konnten durchschnittlich zwischen 0,33 mg/kg und 0,27 mg/kg DON-nachgewiesen werden. 58% der Winterweizenproben wiesen Zearalenon mit einem Maximalgehalt von 1,56 mg/kg auf. Die höchsten ZEA-Werte wurden in Proben ermittelt, die gleichzeitig einen hohen DON-Gehalt aufwiesen. Die Konzentrationen von NIV und T-2 Toxin waren vergleichsweise niedrig. 30% der Proben hatten NIV-Gehalte zwischen 0,04 mg/kg und 0,29 mg/kg und 38% enthielten T-2 Toxin zwischen 0,005 mg/kg und 0,06 mg/kg. In den Futterweizenproben konnte DON als einziges Toxin mit einem Gehalt von durchschnittlich 0,19 mg/kg und maximal 0,75 mg/kg festgestellt werden. Die Weizenmehle, die im October 1987 gezogen wurden, wiesen maximal 0,58 mg/kg DON auf. Die Gehalte lagen damit medriger als die der Mehlproben vom Juni 1988, die maximal 3,24 mg/kg und durchschnittlich 0,26 mg/kg DON enthielten. Dieser Sachverhalt könnte auf Anteile von nicht kontaminiertem Weizen der Ernte 86 an den im October gezogenen Mehlproben zurückgeführt werden. Die Toxingehalte der Vollkornmehle waren nicht höher als die der Weizenmehle der Type 550. Die höchsten Durchschnittsgehalte von DON wurden in Mittel- und Unterfranken festgestellt.