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.     

The day of the week when you were born in 700 ms: Calendar computation in an autistic savant.

Some individuals are able to determine the weekday of a given date in a few seconds (finding for instance that June 12, 1900, was a Tuesday). This ability has fascinated scientists for many years because it is predominantly observed in people with limited intelligence and may appear very early in life. Exceptional visual memory, exceptional concentration abilities, or privileged access to lower levels of information not normally available through introspection have been advanced to explain such phenomena. In the present article, the authors show that a simple cognitive model can explain all aspects of the performance of Donny, a young autistic savant who is possibly the fastest and most accurate calendar prodigy ever described. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

RFID im Blickpunkt wirtschaftlicher Überlegungen

Diese Recherche zeigt, dass sich die Bedeutung, die dem Thema RFID in den Medien und der ?ffentlichen Diskussion derzeit beigemessen wird, auch in der Anzahl der im Internet zu findenden Seiten niederschl?gt. Dabei bewegt sich die Qualit?t der betrachteten Angebote überwiegend auf einem hohen Niveau, was vor allem auf Seiten der kommerziellen Anbieter nicht weiter verwundert, da es sich bei RFID doch um einen zunehmend st?rker umk?mpften Markt handelt, auf dem es hei?t, potenzielle Kunden für sich zu akquirieren. Es darf mit Spannung erwartet werden, wie sich das Informationsangebot wandelt, wenn tats?chlich das prognostizierte exponentielle Wachstum des RFID-Marktes eintritt.     

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.     

Synthesis and thermal stability of ball-milled and melt-quenched amorphous and nanostructured Al-Ni-Nd-Co alloys

In this work the Al₈₅Ni₉Nd₄Co₂ alloy was used as a starting point for examining the possibility of forming bulk glassy Al-based materials by combining rapid quenching and ball milling techniques. Fine glassy powders were obtained by ball milling melt-spun amorphous ribbons using a severe cryogenic processing regime. The thermal stability data of the powders as obtained by constant-rate heating and isothermal DSC experiments together with viscosity measurements are discussed with respect to feasible consolidation conditions. The powder compaction was done by two methods (uni-axial hot pressing and extrusion) at 513 K for up to 15 min. Only the uni-axial hot pressing led to bulk Al₈₅Ni₉Nd₄Co₂ samples with similar glassy structure and Vickers microhardness values comparable to those of the initial melt-spun ribbons.     

The Metaflow architecture

The Metaflow architecture, a unified approach to maximizing the performance of superscalar microprocessors, is introduced. The Metaflow architecture exploits inherent instruction-level parallelism in conventional sequential programs by hardware means, without relying on optimizing compilers. It is based on a unified structure, the DRIS (deferred-scheduling, register-renaming instruction shelf), that manages out-of-order execution and most of the attendant problems. Coupling the DRIS with a speculative-execution mechanism that avoids conditional branch stalls results in performance limited only be inherent instruction-level parallelism and available execution resources. Although presented in the context of superscalar machines, the technique is equally applicable to a superpipelined implementation. Lightning, the first implementation of the Metaflow architecture, which executes the Sparc RISC instruction set is described