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The &alpha, 7 nicotinic acetylcholine receptor (&alpha, 7 nAChR) is a ligand-gated ion channel that is involved in cognition disorders, schizophrenia, pain, and inflammation. Allosteric modulation of this receptor might be advantageous to reduce the toxicity in comparison with full agonists. Our previous results obtained with some hydroxy-chalcones, which were identified as positive allosteric modulators (PAMs) of &alpha, 7 nAChR, prompted us to evaluate the potential of some structurally related naturally occurring flavonoids and curcuminoids and some synthetic curcumin analogues, with the aim of identifying new allosteric modulators of the &alpha, 7 nAChR. Biological evaluation showed that phloretin, demethoxycurcumin, and bis-demethoxicurcuming behave as PAMs of &alpha, 7 nAChR. In addition, some new curcumin derivatives were able to enhance the signal evoked by ACh, the activity values found for the tetrahydrocurcuminoid analog 23 were especially promising.

Antioxidant compounds, including polyphenols, have therapeutic effects because of their anti-inflammatory, antihypertensive, antithrombotic and antiproliferative properties. They play important roles in protecting the cardiovascular and neurological systems, by having preventive or protective effects against free radicals produced by either normal or pathological metabolism in such systems. For instance, resveratrol, a well-known potent antioxidant, has a counteracting effect on the excess of reactive oxygen species (ROS) and has a number of therapeutic benefits, like anti-inflammatory, anti-cancer and cardioprotective activities. Based on previous work from our group, and on the most frequent OH substitutions of natural polyphenols, we designed two series of synthetically accessible bis-polyhydroxyphenyl derivatives, separated by amide or urea linkers. These compounds exhibit high antioxidant ability (oxygen radical absorbance capacity (ORAC) assay) and interesting radical scavenging activity (RSA) values (2,2&prime, azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and &alpha, &alpha, diphenyl-&beta, picrylhydrazyl (DPPH) tests). Some of the best polyphenols were evaluated in two biological systems, endothelial cells (in vitro) and whole aorta (ex vivo), highly susceptible for the deleterious effects of prooxidants under different inflammatory conditions, showing protection against oxidative stress induced by inflammatory stimuli relevant in cardiovascular diseases, i.e., Angiotensin II and IL-1&beta, Selected compounds also showed strong in vivo antioxidant properties when evaluated in the model organism Saccharomyces cerevisiae.

The interaction between vascular endothelial growth factor (VEGF) and its receptors (VEGFR) has important implications in angiogenesis and cancer, which moved us to search for peptide derivatives able to block this protein-protein interaction. In a previous work we had described a collection of linear 13-mer peptides specially designed to adopt helical conformations (Ac-SSEEXARNXAAXN-NH), as well as the evaluation of seven library components for the inhibition of the interaction of VEGF with its Receptor 1 (VEGFR1). This study led to the discovery of some new, quite potent inhibitors of this protein-protein system. The results we found prompted us to extend the study to other peptides of the library. We describe here the evaluation of a new selection of peptides from the initial library that allow us to identify new VEGF-VEGFR1 inhibitors. Among them, the peptide sequence containing F,W, and I residues at the 5, 9, and 12 positions, show a very significant nanomolar IC50 value, competing with VEGF for its receptor 1, VEGFR1 (Flt-1), which could represent a new tool within the therapeutic arsenal for cancer detection and therapy., This work was supported by the Spanish Ministerio de Economía y Competitividad (MINECO) SAF2015-66275-C2-R, subprograma NEF and by the University Paris Descartes and the ANR (Grants ANR-2010-BLANC-1533-03). BBP thanks the CSIC for a predoctoral fellowship (JAE-Predoc from Junta para la Ampliación de Estudios, co-financed by FSE).

The design, synthesis, conformational studies and binding affinity for VEGFR-1 receptors of a collection of linear and cyclic peptide analogues of the β-hairpin fragment VEGF 81–91 are described. Cyclic 11-mer peptide derivatives were prepared from linear precursors with conveniently located Cys, Asp or Dap residues, by the formation of disulfide and amide bridges, using solid-phase synthesis. Molecular modelling studies indicated a tendency to be structured around the central β-turn of the VEGF 81–91 β-hairpin in most synthesized cyclic compounds. This structural behavior was confirmed by NMR conformational analysis. The NHCO cyclic derivative 7 showed significant affinity for VEGFR-1, slightly higher than the native linear fragment, thus supporting the design of mimics of this fragment as a valid approach to disrupt the VEGF/VEGFR-1 interaction.

The α7 acetylcholine nicotine receptor is a ligand-gated ion channel that is involved in cognition disorders, schizophrenia, pain and inflammation among other diseases. Therefore, the development of new agents that target this receptor has great significance. Positive allosteric modulators might be advantageous, since they facilitate receptor responses without directly interacting with the agonist binding site. Here we report the search for and further design of new positive allosteric modulators having the relatively simple chalcone structure. From the natural product isoliquiritigenin as starting point, chalcones substituted with hydroxyl groups at defined locations were identified as optimal and specific promoters of α77 nicotinic function. The most potent compound (2,4,2-2,5-2-tetrahydroxychalcone, 111) was further characterized showing its potential as neuroprotective, analgesic and cognitive enhancer, opening the way for future developments around the chalcone structure.

The 6-substituted benzimidazo[1,2-c]quinazoline 1 is a lead structure from our DNA intercalator program and is cytotoxic to the human colon cancer tumor line HT-29 with an inhibitory concentration 50, IC50 of 4.00 μM. In order to try and improve the limited cytotoxicity of this class of compound we prepared a series consisting of two benzimidazo[1,2-c]quinazoline moieties linked by a polyalkylamino bridge, of different length and substitution. The compound with the -NH-(CH2)3-N(CH3)-(CH2)3-NH-bridge had an inhibitory concentration 50, IC50 of 0.5 μM. When tested in vivo, however, no clear anti-tumor activity was produced in the human breast cancer tumor line MX-1 or the human melanoma tumor line LOX, human tumor xenografts models.

Enediyne anticancer antibiotics are a rapidly emerging class of compounds derived from natural sources. Many synthetic approaches for the construction of simpler compounds containing this pharmacophore have recently been published. Most of these approaches use the quinoline ring as the heterocyclic moiety . In this paper, we describe a synthetic route for the preparation of enediyne systems 14 and 15, which include in their structure a tetrahydropyridine ring and are related to dynemicin A. Their stereochemistries were determined using NOESY and COSY-NMR. Finally, compounds derived from linkage to intercalating carriers, such as a fluorene ring to enediyne 15 or a naphthalimide ring to acyclic enediyne 6, were prepared.

The synthesis of model compounds 1 and 2 related to dynemicin A is described.

The design, synthesis, conformational studies and binding affinity for VEGF receptors of a collection of linear and cyclic peptide analogues of the N-terminal α-helix fragments 13-25 of VEGF and 1-13 of Vammin are described. Linear 13(14)-mer peptides were designed with the help of an AGADIR algorithm and prepared following peptide solid-phase synthetic protocols. Cyclic peptide derivatives were prepared on-resin from linear precursors with conveniently located Glu and Lys residues, by the formation of amide linkages. Conformational analysis, CD and NMR, showed that most synthesized peptides have a clear tendency to be structured as α-helices in solution. Some of the peptides were able to bind a VEGFR-1 receptor with moderate affinity. In addition to the described key residues (Phe17, Tyr21 and Tyr25), Val14 and Val20 seem to be relevant for affinity.

Reaction of iminophosphorane 2 with methyl isocyanate yields the mesoionic 1,3,4-oxadiazolo[3,2-a]pyridinylium-2-methylamindie 3, which undergoes N-methylation with CF3SO3CH3 to give the 1,3,4-oxadiazolo[3,2-a]pyridinium cation 4. The structure of compound 4 has been established by means of X-ray crystallography. Mesoionic aminide 3 undergoes rearrangement by the action of base to give the isomeric mesoionic compound 1,3,4-triazolo[3,2-a]pyridinylium-2-olate 11. Compound 3 by the action of (arylimino)triphenylphosphoranes is converted into the corresponding 1,3,4-oxadiazolo[3,2-a]pyridinylium-2-arylaminides 12, which can be also prepared from iminophosphorane 2 and hydroximoyl chlorides. Iminophosphoran-vermittelte Syntheses von mesoionischen 1,3,4- Oxadiazolo[3,2a]pyridinylium-2-aminiden Das Iminophosphoran 2 reagiert mit Methylisocyanat zu dem mesoionischen 1,3,4-Oxadiazolo[3,2-a]pyridinylium-2-methylaminid 3, das durch CF3SO3CH3 zum 1,3,4-Oxadiazolo[3,2-a]-pyridinium-Kation 4 methyliert wird. Struktur 4 wurde durch Rontgenstrukturanalyse gesichert. Durch Einwirkung von Base lagert das mesoionische Aminid 3 zum isomeren mesoionischen 1,3,4-Triazolo[3,2-a]pyridinylium-2-olat 11 um. Verbindung 3 wird durch (Arylimino)triphenylphosphorane in die entsprechenden 1,3,4-Oxadiazolo[3,2-a]pyridinium-2-arylaminide 12 umgewandelt, die auch aus Iminophosphoran 2 und Hydroximoylchloriden zuganglich sind.