Repositioning of Quinazolinedione-Based Compounds on Soluble Epoxide Hydrolase (sEH) through 3D Structure-Based Pharmacophore Model-Driven Investigation

The development of new bioactive compounds represents one of the main purposes of the drug discovery process. Various tools can be employed to identify new drug candidates against pharmacologically relevant biological targets, and the search for new approaches and methodologies often represents a critical issue. In this context, in silico drug repositioning procedures are required even more in order to re-evaluate compounds that already showed poor biological results against a specific biological target. 3D structure-based pharmacophoric models, usually built for specific targets to accelerate the identification of new promising compounds, can be employed for drug repositioning campaigns as well. In this work, an in-house library of 190 synthesized compounds was re-evaluated using a 3D structure-based pharmacophoric model developed on soluble epoxide hydrolase (sEH). Among the analyzed compounds, a small set of quinazolinedione-based molecules, originally selected from a virtual combinatorial library and showing poor results when preliminarily investigated against heat shock protein 90 (Hsp90), was successfully repositioned against sEH, accounting the related built 3D structure-based pharmacophoric model. The promising results here obtained highlight the reliability of this computational workflow for accelerating the drug discovery/repositioning processes.     

Phloretin,as a Potent Anticancer Compound: From Chemistry to Cellular Interactions

Phloretin is a natural dihydrochalcone found in many fruits and vegetables, especially in apple tree leaves and the Manchurian apricots, exhibiting several therapeutic properties, such as antioxidant, antidiabetic, anti-inflammatory, and antitumor activities. In this review article, the diverse aspects of the anticancer potential of phloretin are addressed, presenting its antiproliferative, proapoptotic, antimetastatic, and antiangiogenic activities in many different preclinical cancer models. The fact that phloretin is a planar lipophilic polyphenol and, thus, a membrane-disrupting Pan-Assay Interference compound (PAIN) compromises the validity of the cell-based anticancer activities. Phloretin significantly reduces membrane dipole potential and, therefore, is expected to be able to activate a number of cellular signaling pathways in a non-specific way. In this way, the effects of this minor flavonoid on Bax and Bcl-2 proteins, caspases and MMPs, cytokines, and inflammatory enzymes are all analyzed in the current review. Moreover, besides the anticancer activities exerted by phloretin alone, its co-effects with conventional anticancer drugs are also under discussion. Therefore, this review presents a thorough overview of the preclinical anticancer potential of phloretin, allowing one to take the next steps in the development of novel drug candidates and move on to clinical trials.     

Design,Synthesis and Biological Evaluation of Simplified Analogues of the Major Corn Strigolactones,Zealactone and Zeapyranolactone

Strigolactones are one of the phytohormones, which have multiple activities on plant growth and development. Since these strigolactone activities are highly associated with crop yield, use of strigolactone could be a promising technology in modern sustainable agriculture. The major strigolactones in corn root exudates have been identified as zealactone 1a/b and zeapyranolactone. We recently disclosed the first total synthesis of zealactone 1a/b together with its biological activity in corn. Herein, we describe the design and synthesis of simplified analogues of both corn-derived strigolactones with their bioavailability in soil and their biological activities. These compounds would be potential leads for the development of synthetic strigolactones for the agronomical use in a more sustainable crop production.     

Biodegradable High-Density Polyethylene-like Material

We report a novel polyester material generated from readily available biobased 1,18-octadecanedicarboxylic acid and ethylene glycol possesses a polyethylene-like solid-state structure and also tensile properties similar to high density polyethylene (HDPE). Despite its crystallinity, high melting point (T_m=96 °C) and hydrophobic nature, polyester-2,18 is subject to rapid and complete hydrolytic degradation in in vitro assays with isolated naturally occurring enzymes. Under industrial composting conditions (ISO standard 14855-1) the material is biodegraded with mineralization above 95 % within two months. Reference studies with polyester-18,18 (T_m=99 °C) reveal a strong impact of the nature of the diol repeating unit on degradation rates, possibly related to the density of ester groups in the amorphous phase. Depolymerization by methanolysis indicates suitability for closed-loop recycling.     

A Three-dimensional Continuum Theory of Dislocation Plasticity - Modelling and Application to a Composite

The increasing demand for materials with well defined microstructure, which is accompanied by the advancing miniaturization of devices calls for physically motivated, dislocation-based continuum theories of plasticity. Only recently rigorous techniques have been developed for performing meaningful averages over systems of moving, curved dislocations, yielding evolution equations for a higher order dislocation density tensor. Our continuum dislocation theory allows for generalizing the planar system towards a three-dimensional system, where dislocations may have arbitrary orientation and curvature. With the inclusion of curvature, the theory naturally takes into account a deformation-induced increase in the overall dislocation density without having to invoke ad-hoc assumptions about dislocation sources. A numerical implementation and some benchmark tests of this continuum theory for dislocation dynamics has already been discussed in the literature. In this paper, we apply this continuum theory to composite materials, where we analyze a plastically deforming matrix with an elastic inclusion. (© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim)     

Stereoselective Synthesis and Biological Profile of All Stereoisomers of Lactam Analogues of Strigolactones GR24 and GR18

Strigolactones (SLs) are signaling molecules involved in plant development and governing interactions with soil microorganisms in the rhizosphere as well as the germination of parasitic weeds. Developing their use in Crop Protection is a promising approach to a sustainable agriculture by mitigating biotic and abiotic stresses. Recently, a new class of lactam analogues of SL has emerged, namely strigolactams, displaying outstanding potency to induce the germination of parasitic weed O. cumana as well as enhanced chemical and soil stability. Herein, we describe the stereoselective synthesis of GR24 and GR18 lactams harnessing the chemistry of chiral keteniminium (KI) salts, in particular the unprecedented reactivity of chloro-substituted KI, supported by DFT calculations. We disclose subsequently the biological activity on corn of the 32 stereopure strigolactams prepared, highlighting the crucial influence of stereochemistry and lactam substitution, rationalized by docking analyses. Finally, we performed stability studies in soil, which reveal that stereoisomers display very different half-lives, reflecting the significant impact of stereochemistry on degradation kinetics.     

Optical probing and imaging of live cells using SERS labels

During surface‐enhanced Raman scattering (SERS), molecules exhibit a significant increase in their Raman signals when attached, or in very close vicinity, to gold or silver nanostructures. This effect is exploited as the basis of a new class of optical labels. Here we demonstrate robust and sensitive SERS labels as probes for imaging live cells. These hybrid labels consist of gold nanoparticles with Rose Bengal or Crystal Violet attached as reporter molecules. These new labels are stable and nontoxic, do not suffer from photobleaching, and can be excited at any excitation wavelength, even in the near infrared. SERS labels can be detected and imaged through the specific Raman signatures of the reporters. In addition, surface‐enhanced Raman spectroscopy in the local optical fields of the gold nanoparticles also provides sensitive information on the immediate molecular environment of the label in the cell and allows imaging of the native constituents of the cell. This is demonstrated by images based on a characteristic Raman line of the reporter as well as by displaying lipids based on the SERS signal of the C H deformation/bending modes at ∼1470 cm⁻¹. Copyright © 2008 John Wiley & Sons, Ltd.     

ChemInform Abstract: Theoretical Studies of Inorganic Compounds. Part 19. Quantum Chemical Investigations of the Phosphane Complexes X3B‐PY3 and X3Al‐PY3 (X: H,F, Cl; Y: F,Cl, Me,CN).

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