Synthetic lethality is an innovative framework for discovering novel anticancer drug candidates. One example is the use of PARP inhibitors (PARPi) in oncology patients with BRCA mutations. Here, we exploit a new paradigm based on the possibility of triggering synthetic lethality using only small organic molecules (dubbed “fully small-molecule-induced synthetic lethality”). We exploited this paradigm to target pancreatic cancer, one of the major unmet needs in oncology. We discovered a dihydroquinolone pyrazoline-based molecule ( 35d ) that disrupts the RAD51-BRCA2 protein–protein interaction, thus mimicking the effect of BRCA2 mutation. 35d inhibits the homologous recombination in a human pancreatic adenocarcinoma cell line. In addition, it synergizes with olaparib (a PARPi) to trigger synthetic lethality. This strategy aims to widen the use of PARPi in BRCA -competent and olaparib-resistant cancers, making fully small-molecule-induced synthetic lethality an innovative approach toward unmet oncological needs.

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A small library of sugar-modified guanosine derivatives has been prepared, starting from a common intermediate, fully protected on the nucleobase. Insertion of myristoyl chains and of diverse hydrophilic groups, such as an oligoethylene glycol, an amino acid or a disaccharide chain, connected through in vivo reversible ester linkages, or of a charged functional group provided different examples of amphiphilic guanosine analogues, named G1-G7 herein. All of the sugar-modified derivatives were positive in the potassium picrate test, showing an ability to form G-tetrads. CD spectra demonstrated that, as dilute solutions in CHCl(3), distinctive G-quadruplex systems may be formed, with spatial organisations dependent upon the structural modifications. Two compounds, G1 and G2, proved to be good low-molecular-weight organogelators in polar organic solvents, such as methanol, ethanol and acetonitrile. Ion transportation experiments through phospholipid bilayers were carried out to evaluate their ability to mediate H(+) transportation, with G5 showing the highest activity within the investigated series. Moreover, G3 and G5 exhibited a significant cytotoxic profile against human MCF-7 cancer cells in in vitro bioassays.

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The [Pd(dppp)(OTf)2] complex acts as an efficient transporter of halide anions, in particular the biologically relevant chloride anion, across a phospholipid bilayer.

A As ss se es ss sm me en nt t o of f p pl la an nt ts s/ /h he er rb bs s a an nd d e ex xt tr ra ac ct ts s I In nt tr ro od du uc ct ti io on n 5 5 M Mo on no og gr ra ap ph hs s o of f t th he e f fo ol ll lo ow wi in ng g s sp pe ec ci ie es s: : FOREWORDIn September 2003 the European Parliament and the Council of the European Union adopted the Regulation No. 1831/2003 on additives for use in animal nutrition. The purpose of this regulation is to establish a Community procedure for authorising the placing on the market and use of feed additives and to lay down rules for the supervision and labelling of feed additives and premixtures in order to provide the basis for the assurance of a high level of protection of human health, animal health and welfare, environment, and "users and consumers" interests in relation to feed additives, whilst ensuring the effective functioning of the internal market. Under the current regulation detailed guidelines for some family of products are completely missing, that it is the case of the plants/herbs, plant/herb extracts and their naturally or synthetically produced components. For this reason it is one of the priorities of the FEEDAP Panel to implement guidelines/guidance for these types of compounds.It has been observed that plant/herbs and their extracts are increasingly being used (and informally marketed) not only as sensory additives, but also for other purposes not covered by the legislation, notably better growth or feed conversion, improved meat quality, and for prophylactic purposes. There are strong indications that such use will further increase as replacement additives for the antibiotic growth promoters whose use will be prohibited by the end of 2005.Nowadays, a compiled list of these compounds or extracts does not exists although the European Federation of Animal Feed Additive Manufacturers (FEFANA) notes that some 280 plant extracts and a further 1700 chemically defined compounds have been used within Member States as sensory additives in animal feeds.The results of this study will be used by EFSA, in consultation with the European Commission, Member States and other stakeholders, to provide input for the development of guidance/guidelines documents for the authorisation of plants/herbs, plant/herb extracts and their naturally or synthetically produced components for use in animal nutrition. ASSESSMENT OF PLANTS/HERBS, PLANT/HERB EXTRACTS AND THEIR NATURALLY OR SYNTHETICALLY PRODUCED COMPONENTS AS "ADDITIVES" FOR USE INTRODUCTIONThe last two decades have seen a substantial increase in use of herbs/botanicals and their products not only as herbal medicinal products and for food supplements, but also in the field of animal nutrition. The use of herbal feed additives, which include essential oils and (exotic) herbal mixtures, is extensively promoted by the producers, but the scientific background underpinning their use often is limited. Consequently an adequate knowledge of quality control (content of active substance(s) stability), efficacy and safety is oft...

We take advantage of the Pummerer oxidative annulation reaction to extend PAHs through the formation of an intramolecular C−O bond with a suitable phenol substituent. Depending on the peripheral topology of the PAH precursor (e.g., pyrene, boron-dipyrromethene or perylene bisimide) five-, six-and seven-member O-containing rings could be obtained. The effect of the Oannulation on the optoelectronic properties was studied by various methods, with the pyrano-annulated pyrene and BODIPY derivatives depicting quantitative emission quantum yields.

An efficient protocol for the solid-phase synthesis of six members of a new class of extended macrocyclic peptoids (based on ortho-, meta- and para-N-(methoxyethyl)aminomethyl phenylacetyl units) is described. Theoretical (DFT) and experimental (NMR) studies on the free and Na-complexed cyclic trimers (3-5) and tetramers (6-8) demonstrate that annulation of the rigidified peptoids can generate new hosts with the ability to sequestrate one or two sodium cations with the affinities and stoichiometries defined by the macrocycle morphology. Ion transport studies have been also performed in order to better appreciate the factors promoting transmembrane cation translocation.