Natural Products Extracted from Fungal Species as New Potential Anti-Cancer Drugs: A Structure-Based Drug Repurposing Approach Targeting HDAC7

Mushrooms can be considered a valuable source of natural bioactive compounds with potential polypharmacological effects due to their proven antimicrobial, antiviral, antitumor, and antioxidant activities. In order to identify new potential anticancer compounds, an in-house chemical database of molecules extracted from both edible and non-edible fungal species was employed in a virtual screening against the isoform 7 of the Histone deacetylase (HDAC). This target is known to be implicated in different cancer processes, and in particular in both breast and ovarian tumors. In this work, we proposed the ibotenic acid as lead compound for the development of novel HDAC7 inhibitors, due to its antiproliferative activity in human breast cancer cells (MCF-7). These promising results represent the starting point for the discovery and the optimization of new HDAC7 inhibitors and highlight the interesting opportunity to apply the “drug repositioning” paradigm also to natural compounds deriving from mushrooms.     

Copper and iron interactions with angiotensin-converting enzyme inhibitors. A study by fast-atom bombardment tandem mass spectrometry

Fast atom bombardment, combined with high-energy collision-induced tandem mass spectrometry, has been used to investigate gas-phase metal-ion interactions with captopril, enalaprilat and lisinopril, all angiotensin-converting enzyme inhibitors.Suggestions for the location of metal-binding sites are presented. For captopril, metal binding occurs most likely at both the sulphur and the nitrogen atom. For enalaprilat and lisinopril, binding preferably occurs at the amine nitrogen. Copyright 1999 John Wiley & Sons, Ltd.     

ESI‐MS/MS of expanded porphyrins: a look into their structure and aromaticity

Electrospray mass spectrometry/mass spectrometry was used to investigate the gas‐phase properties of protonated expanded porphyrins, in order to correlate those with their structure and conformation. We have selected five expanded meso‐pentafluorophenyl porphyrins, respectively, a pair of oxidized/reduced fused pentaphyrins (22 and 24 π electrons), a pair of oxidized/reduced regular hexaphyrins (26 and 28 π electrons) and a regular doubly N‐fused hexaphyrin (28 π electrons). The gas‐phase behavior of the protonated species of oxidized and reduced expanded porphyrins is different. The oxidized species (aromatic Hückel systems) fragment more extensively, mainly by the loss of two HF molecules. The reduced species (Möbius aromatic or Möbius‐like aromatic systems) fragment less than their oxidized counterparts because of their increased flexibility. The protonated regular doubly fused hexaphyrin (non‐aromatic Hückel system) shows the least fragmentation even at higher collision energies. In general, cyclization through losses of HF molecules decreases from the aromatic Hückel systems to Möbius aromatic or Möbius‐like aromatic systems to non‐aromatic Hückel systems and is related to an increase in conformational distortion. Copyright © 2016 John Wiley & Sons, Ltd.     

The influence of temperature on limestone sulfation and attrition under fluidized bed combustion conditions

The influence of temperature on attrition of two limestones during desulfurization in a fluidized bed reactor was investigated. Differences in the microstructure of the two limestones were reflected by a different thickness of the sulfate shell formed upon sulfation and by a different value of the ultimate calcium conversion degree. Particle attrition and fragmentation were fairly small under moderately bubbling fluidization conditions for both limestones. An increase of temperature from 850 °C to 900 °C led to an increase of the attrition rate, most likely because of a particle weakening effect caused by a faster CO₂ evolution during calcination. This weakening effect, however, was not sufficiently strong to enhance particle fragmentation in the bed. The progress of sulfation, associated to the build-up of a hard sulfate shell around the particles, led in any case to a decrease of the extent of attrition. Sulfation at 900 °C was less effective than at 850 °C, and this was shown to be related to the porosimetric features of the different samples.     

Devolatilization and ash comminution of two different sewage sludges under fluidized bed combustion conditions

Two different wet sewage sludges have been characterized under fluidized bed combustion conditions with reference to their devolatilization behavior and ash comminution with the aid of different and complementary experimental protocols. Analysis of the devolatilization process allowed to determine the size of fuel particle able to achieve effective lateral spreading of the volatile matter across the cross-section of medium-scale combustors. Primary fragmentation and primary ash particle characterization pointed out the formation of a significant amount of relatively large fragments. The mechanical properties of these fragments have been characterized by means of elutriation/abrasion tests using both quartz and sludge ash beds.     

Investigating the vortex melting phenomenon in BSCCO crystals using magneto-optical imaging technique

Using a novel differential magneto-optical imaging technique we investigate the phenomenon of vortex lattice melting in crystals of Bi₂Sr₂CaCu₂O₈ (BSCCO). The images of melting reveal complex patterns in the formation and evolution of the vortex solid-liquid interface with varying field (H)/temperature (T). We believe that the complex melting patterns are due to a random distribution of material disorder/inhomogeneities across the sample, which create fluctuations in the local melting temperature or field value. To study the fluctuations in the local melting temperature/field, we have constructed maps of the melting landscape T _m(H, r), viz., the melting temperature (T _m) at a given location (r) in the sample at a given field (H). A study of these melting landscapes reveals an unexpected feature: the melting landscape is not fixed, but changes rather dramatically with varying field and temperature along the melting line. It is concluded that the changes in both the scale and shape of the landscape result from the competing contributions of different types of quenched disorder which have opposite effects on the local melting transition.     

Energy dependence of multiplicity in proton-nucleus collisions and models of multiparticle production

This is a continuation of our earlier investigation (Gurtuet al 1974Phys. Lett. 50 B 391) on multiparticle production in proton-nucleus collisions based on an exposure of emulsion stack to 200 GeV/c beam at the NAL. It is found that the ratioR _em = 〈n _s〉/〈n _ch〉, where 〈n _ch〉 is the charged particle multiplicity in pp-collisions, increases slowly from about 1 at 10 GeV/c to 1·6 at 68 GeV/c and attains a constant value of 1·71 ± 0·04 in the region 200 to 8000 GeV/c. Furthermore,R _em = 1·71 implies an effectiveA-dependence ofR _A =A ^0.18,i.e., a very weak dependence. Predictions ofR _em on various models are discussed and compared with the emulsion data. Data seem to favour models of hadron-nucleon collisions in which production of particles takes place through adouble step mechanism,e.g., diffractive excitation, hydrodynamical and energy flux cascade as opposed to models which envisage instantaneous production.     

Tri-partite complex for axonal transport drug delivery achieves pharmacological effect

Background

Targeted delivery of pharmaceutical agents into selected populations of CNS (Central Nervous System) neurons is an extremely compelling goal. Currently, systemic methods are generally used for delivery of pain medications, anti-virals for treatment of dermatomal infections, anti-spasmodics, and neuroprotectants. Systemic side effects or undesirable effects on parts of the CNS that are not involved in the pathology limit efficacy and limit clinical utility for many classes of pharmaceuticals. Axonal transport from the periphery offers a possible selective route, but there has been little progress towards design of agents that can accomplish targeted delivery via this intraneural route. To achieve this goal, we developed a tripartite molecular construction concept involving an axonal transport facilitator molecule, a polymer linker, and a large number of drug molecules conjugated to the linker, then sought to evaluate its neurobiology and pharmacological behavior.

Results

We developed chemical synthesis methodologies for assembling these tripartite complexes using a variety of axonal transport facilitators including nerve growth factor, wheat germ agglutinin, and synthetic facilitators derived from phage display work. Loading of up to 100 drug molecules per complex was achieved. Conjugation methods were used that allowed the drugs to be released in active form inside the cell body after transport. Intramuscular and intradermal injection proved effective for introducing pharmacologically effective doses into selected populations of CNS neurons. Pharmacological efficacy with gabapentin in a paw withdrawal latency model revealed a ten fold increase in half life and a 300 fold decrease in necessary dose relative to systemic administration for gabapentin when the drug was delivered by axonal transport using the tripartite vehicle.

Conclusion

Specific targeting of selected subpopulations of CNS neurons for drug delivery by axonal transport holds great promise. The data shown here provide a basic framework for the intraneural pharmacology of this tripartite complex. The pharmacologically efficacious drug delivery demonstrated here verify the fundamental feasibility of using axonal transport for targeted drug delivery.