Molecular basis of phospholipase A2 inhibition by petrosaspongiolide M.

Petrosaspongiolide M (PM) is an anti-inflammatory marine metabolite that displays a potent inhibitory activity toward group II and III secretory phospholipase A2 (PLA2) enzymes. The details of the mechanism, which leads to a covalent adduct between PLA2 and γ-hydroxybutenolide-containing molecules such as PM, are still a matter of debate. In this paper the covalent binding of PM to bee venom PLA2 has been investigated by mass spectrometry and molecular modeling. The mass increment observed for the PM-PLA2 adduct is consistent with the formation of a Schiff base by reaction of a PLA2 amino group with the hemiacetal function (masked aldehyde) at the C-25 atom of the PM γ-hydroxybutenolide ring. Proteolysis of the modified PLA2 by the endoprotease LysC followed by HPLC MS analysis allowed us to establish that the PLA2 α-amino terminal group of the lle-1 residue was the only covalent binding site for PM. The stoichiometry of the reaction between PM and PLA2 was also monitored and results showed that even with excess inhibitor, the prevalent product is a 1:1 (inhibitor:enzyme) adduct, although a 2:1 adduct is present as a minor component. The 2:1 adduct was also characterized, which showed that the second site of reaction is located at the ε-amino group of the Lys-85 residue. Similar results in terms of the reaction profile, mass increments, and location of the PLA2 binding site were obtained for manoalide, a paradigm for irreversible PLA2 inhibitors, which suggests that the present results may be considered of more general interest within the field of anti-inflammatory sesterterpenes that contain the γ-hydroxybutenolide pharmacophore. Finally, a 3D model, constrained by the above experimental results, was obtained by docking the inhibitor molecule into the PLA2 binding site through AFFINITY calculations. The model provides an interesting insight into the PM-PLA2 inhibition process and may prove useful in the design of new anti-inflammatory agents that target PLA2 secretory enzymes

“I luoghi di Mercalli”: a travelling exhibition as a tool for scientists to dialogue with the public on volcanoes and earthquakes

On March 19, 1914 Giuseppe Mercalli, a seismologist and volcanologist, well-known around the world for the Intensity scale of earthquakes bearing his name, died tragically. A hundred years after, the Istituto Nazionale di Geofisica e Vulcanologia (INGV) has promoted a variety of activities and cultural events that will take place under the Patronage of the President of the Italian Republic within a year, the so called “Anno Mercalliano” (the Year of Mercalli). The opening ceremony took place in Naples, Italy, on March 19, 2014, in the Convitto Nazionale Vittorio Emanuele II. A scientific conference was held with the participation of experts from INGV and the university of Milano – Bicocca, and presentations of students. On that day the exhibition entitled “I luoghi di Mercalli” (Mercalli's places) was also inaugurated, at the presence of local authorities. The exhibition, organized by INGV, was realized in collaboration with the high school Vittorio Emanuele II, where Mercalli has been teaching for 19 years, and the Università degli Studi Suor Orsola Benincasa, where he was professor of natural sciences. A biographical and geographical description of the places where Mercalli operated introduces the exhibition, which is organized in sections: - Mercalli educator (he taught at high schools in Reggio Calabria and Naples); - Mercalli volcanologist (Mercalli studied Vesuvius volcanic activity for more than twenty years, he was a scientific witness of the Vesuvius 1906 eruption, and of the eruptions occurred at Vulcano (1888-90) and Stromboli (1891) islands. - Mercalli seismologist (Mercalli Intensity scale definition, based on his experience as witness of catastrophic earthquakes, such as Casamicciola in 1883 and Messina in 1908). Another section deals with the Vesuvius Observatory, directed by Mercalli between 1911 and 1914, and the description of the three active volcanoes of the Campania region (Vesuvius, Campi Flegrei and Ischia island), which have been the subject of studies by the well-known scientist. The exhibition is enriched by documents, manuscripts, photos and field notebooks of Mercalli. It is not intended to be only a celebratory exhibition; rather it is designed as a tool for dissemination of scientific culture and to raise awareness about seismic and volcanic hazards. In the exhibition path a continuous thread between the figure of Mercalli as a researcher and the role of an Earth Science researcher today is highlighted, pointing to the development of scientific knowledge in the past century. The goal is to improve the capability of learning from the disasters occurred in the past to implement preventive actions to safely deal with future events. The exhibition is travelling and will be provided on request to institutions and schools.PublishedMilano, Italia1V. Storia e struttura dei sistemi vulcaniciope

The first total synthesis of (+)-mucosin

The first total synthesis of (+)-mucosin has been completed allowing assignment of the absolute stereochemistry of the natural product. A zirconium induced co-cyclisation was utilised to install the correct stereochemistry of the four contiguous stereocentres around the unusual bicyclo[4.3.0]nonene core

Preclinical Pharmacology of BA-TPQ, a Novel Synthetic Iminoquinone Anticancer Agent

Marine natural products and their synthetic derivatives represent a major source of novel candidate anti-cancer compounds. We have recently tested the anti-cancer activity of more than forty novel compounds based on an iminoquinone makaluvamine scaffold, and have found that many of the compounds exert potent cytotoxic activity against human cancer cell lines. One of the most potent compounds, BA-TPQ [(11,12),7-(benzylamino)-1,3,4,8-tetrahydropyrrolo[4,3,2-de]quinolin-8(1H)-one], was active against a variety of human cancer cell lines, and inhibited the growth of breast and prostate xenograft tumors in mice. However, there was some toxicity noted in the mice following administration of the compound. In order to further the development of BA-TPQ, and in a search for potential sites of accumulation that might underlie the observed toxicity of the compound, we accomplished preclinical pharmacological studies of the compound. We herein report the in vitro and in vivo pharmacological properties of BA-TPQ, including its stability in plasma, plasma protein binding, metabolism by S9 enzymes, and plasma and tissue distribution. We believe these studies will be useful for further investigations, and may be useful for other investigators examining the use of similar compounds for cancer therapy

L'autobiografia di Arcangela Biondini. Studi e testo critico

Si tratta dell'edizione critica dell'autobiografia della fondatrice Arcangela Biondini (1641-1712

L'Autobiografia di Arcangela Biondini. Studi e testo critico

Si tratta dell'edizione critica dell'autobiografia della fondatrice Arcangela Biondini (1641-1712

New Bisindole Alkaloids of the Topsentin and Hamacanthin classes from the Mediterranean marine sponge Rhaphisia lacazei.

Chemical investigation of the Et2O extract of the marine sponge Rhaphisia lacazei resulted in the isolation of 13 pure bisindole alkaloids (1-13). Compounds (1-6) belong to the class of topsentins and have already been described. Compounds 7-13 are new products, closely related to the class of hamacanthins. The major compounds 1-3 were tested in vitro for antitumor activity; compounds 2 and 3 showed antiproliferative activity against human broncopulmonary cancer cells (NSCLC-N6) with an IC50 of 12 and 6.3 íg/mL, respectivel