Careful regulation of mRNA half-lives is a fundamental mechanism allowing cells to quickly respond to changing environmental conditions. The mRNA-binding Hu proteins are important for stabilization of short-lived mRNAs. Here we describe the identification and mechanistic characterization of the first low-molecular-weight inhibitors for Hu protein R (HuR) from microbial broths (Actinomyces sp.): dehydromutactin (1), MS-444 (2) and okicenone (3). These compounds interfere with HuR RNA binding, HuR trafficking, cytokine expression and T-cell activation. A mathematical and experimental analysis of the compounds' mode of action suggests that HuR homodimerizes before RNA binding and that the compounds interfere with the formation of HuR dimers. Our results demonstrate the chemical drugability of HuR; to our knowledge HuR is the first example of a drugable protein within the Hu family. MS-444, dehydromutactin and okicenone may become valuable tools for studying HuR function. An assessment of HuR inhibition as a central node in malignant processes might open up new conceptual routes toward combatting cancer.

No abstract

No abstract

Four different FTIR methodsssingle-bead FTIR, beam condenser, macro attenuated total reflection (macro-ATR), and KBr pellet methodssand macro and single-bead FT Raman methods have been investigated, and the relative utility was compared for the analysis of resin-bound organic compounds and the monitoring of solid-phase organic reactions. Furthermore, the comparison includes two additional methods from the literature: diffuse reflectance infrared Fourier transform spectroscopy and photoacoustic spectroscopy. While all of these methods have some utility for solid-phase sample analysis, the relative merits of these methods vary particularly in such areas as the information content, spectral quality, sensitivity, speed, sample requirement, and the instrument cost. Both single-bead FTIR and beam condenser FTIR methods have been found to be superb methods in each of these aspects. In the following way, these methods meet many of the essential requirements for a thin layer chromatography (TLC) equivalent for solid-phase synthesis:(1) Only a single bead or 50-100 beads are needed for analysis so that reaction is not interrupted and is monitored in real-time. (2) A high-quality spectrum can be recorded within a few minutes. (3) No sample preparation is required, making the analysis time even shorter than that for TLC analysis. (4) These two FTIR methods provide qualitative, quantitative (the percentage of conversion), and kinetics information on organic reactions carried out on resin supports. Finally, from the synthetic chemist's point of view, the additional advantages of the beam condenser method, such as the low cost and the ease of operation, make it a more suitable choice as a TLC equivalent for solid-phase organic synthesis applications.

The structures of six novel spirodihydrobenzofuranlactams I~VI (1~6) were determined by spectroscopic methods.Six novel spirodihydrobenzofuranlactams I~VI (16 ) (Fig. 1) have been identified in extracts of two different Stachybotrys species as antagonists of endothelin and as inhibitors of HIV-1 protease. In a recently published paper1} we described the fermentation, isolation and biological properties of these secondary metabolites 1~6. Besides this novel class of the spirodihydrobenzofurans including the lactams 1~4, 6 and the imide 5 the known spirodihydrobenzofuranalcohol L-67 1 7762) was isolated. This inositol-phosphate phosphatase and HIV-1 protease