Discovery of Selective Inhibitors for In Vitro and In Vivo Interrogation of Skeletal Myosin II.

Myosin IIs, actin-based motors that utilize the chemical energy of adenosine 5'-triphosphate (ATP) to generate force, have potential as therapeutic targets. Their heavy chains differentiate the family into muscle (skeletal [SkMII], cardiac, smooth) and nonmuscle myosin IIs. Despite the therapeutic potential for muscle disorders, SkMII-specific inhibitors have not been reported and characterized. Here, we present the discovery, synthesis, and characterization of "skeletostatins," novel derivatives of the pan-myosin II inhibitor blebbistatin, with selectivity 40- to 170-fold for SkMII over all other myosin II family members. In addition, the skeletostatins bear improved potency, solubility, and photostability, without cytotoxicity. Based on its optimal in vitro profile, MT-134's in vivo tolerability, efficacy, and pharmacokinetics were determined. MT-134 was well-tolerated in mice, impaired motor performance, and had excellent exposure in muscles. Skeletostatins are useful probes for basic research and a strong starting point for drug development.

[Air pollution and mortality in twenty-five Italian cities: results of the EpiAir2 Project]. / Inquinamento atmosferico e mortalità in venticinque città italiane: risultati del progetto EpiAir2.

OBJECTIVES: this study aims at presenting the results from the Italian EpiaAir2 Project on the short-term effects of air pollution on adult population (35+ years old) in 25 Italian cities. DESIGN: the short-term effects of air pollution on resident people died in their city were analysed adopting the time series approach. The association between increases in 10µg/m(3) in PM10, PM2.5, NO2 and O3 air concentration and natural, cardiac, cerebrovascular and respiratory mortality was studied. City-specific Poisson models were fitted to estimate the association of daily concentrations of pollutants with daily counts of deaths. The analysis took into account temporal and meteorological factors to control for potential confounding effect. Pooled estimates have been derived from random effects meta-analysis, evaluating the presence of heterogeneity in the city specific results. SETTING AND PARTICIPANTS: it was analysed 422,723 deaths in the 25 cities of the project among people aged 35 years or more, resident in each city during the period 2006-2010. MAIN OUTCOME MEASURES: daily counts of natural, cardiac, cerebrovascular, and respiratory mortality, obtained from the registries of each city. Demographic information were obtained by record linkage procedure with the civil registry of each city. RESULTS: mean number of deaths for natural causes ranged from 513 in Rovigo to 20,959 in Rome. About 25% of deaths are due to cardiac diseases, 10% to cerebrovascular diseases, and 7% to respiratory diseases. It was found an immediate effect of PM10 on natural mortality (0.51%; 95%CI 0.16-0.86; lag 0-1). More relevant and prolonged effects (lag 0-5) have been found for PM2.5 (0.78%; 95%CI 0.12-1.46) and NO2 (1.10%; 95%CI 0.63-1.58). Increases in cardiac mortality are associated with PM10 (0.93%; 95%CI 0.16-1.70) and PM2.5 (1.25%; 95%CI 0.17-2.34), while for respiratory mortality exposure to NO2 has an important role (1.67%; 95%CI 0.23-3.13; lag 2-5), as well as PM10 (1.41%; 95%CI - 0.23;+3.08). Results are strongly homogeneous among cities, except for respiratory mortality. No effect has been found for cerebrovascular mortality and weak evidence of association has been observed between ozone and mortality. CONCLUSIONS: a clear increase in mortality associated to air pollutants was observed. More important are the effects of NO2 (on natural mortality), mostly associated with traffic emissions, and of PM2.5 (on cardiac and respiratory mortality). Nitrogen dioxide shows an independent effect from the particulate matter, as observed in the bi-pollutant models.

Synthesis of both possible isomers of the northwest quadrant of altromycin B.

The synthesis of the northwest quadrant of Altromycin B is described. The preparation of the two epimers at the quaternary carbon of the 6-deoxy-C-altrose moiety in the northwest quadrant is accomplished starting from d-glucose. A key step of our synthetic sequence is the formation of the C-glycoside linkage via the Ramberg-Bäcklund reaction. Two different routes are explored, which differ mainly on the timing of the conversion of glucose to altrose, either before or after the preparation of the C-glycoside. The conformation behavior of variously substituted C-altropyranoside rings is also discussed.