n-Tuples on Scaffold Diversity Inspired by Drug Hybridisation to Enhance Drugability: Application to Cytarabine.

A mathematical concept, n-tuples are originally applied to medicinal chemistry, especially with the creation of scaffold diversity inspired by the hybridisation of different commercial drugs with cytarabine, a synthetic arabinonucleoside derived from two marine natural products, spongouridine and spongothymidine. The new methodology explores the virtual chemical-factorial combination of different commercial drugs (immunosuppressant, antibiotic, antiemetic, anti-inflammatory, and anticancer) with the anticancer drug cytarabine. Real chemical combinations were designed and synthesised for 8-duples, obtaining a small representative library of interesting organic molecules to be biologically tested as proof of concept. The synthesised library contains classical molecular properties regarding the Lipinski rules and/or beyond rules of five (bRo5) and is represented by the covalent combination of the anticancer drug cytarabine with ibuprofen, flurbiprofen, folic acid, sulfasalazine, ciprofloxacin, bortezomib, and methotrexate. The insertion of specific nomenclature could be implemented into artificial intelligence algorithms in order to enhance the efficiency of drug-hunting programs. The novel methodology has proven useful for the straightforward synthesis of most of the theoretically proposed duples and, in principle, could be extended to any other central drug.

Exploring the Antiangiogenic Potential of Solomonamide A Bioactive Precursors: In Vitro and in Vivo Evidences of the Inhibitory Activity of Solo F-OH During Angiogenesis.

Marine sponges are a prolific source of bioactive compounds. In this work, the putative antiangiogenic potential of a series of synthetic precursors of Solomonamide A, a cyclic peptide isolated from a marine sponge, was evaluated. By means of an in vitro screening, based on the inhibitory activity of endothelial tube formation, the compound Solo F-OH was selected for a deeper characterization of its antiangiogenic potential. Our results indicate that Solo F-OH is able to inhibit some key steps of the angiogenic process, including the proliferation, migration, and invasion of endothelial cells, as well as diminish their capability to degrade the extracellular matrix proteins. The antiangiogenic potential of Solo F-OH was confirmed by means of two different in vivo models: the chorioallantoic membrane (CAM) and the zebrafish yolk membrane (ZFYM) assays. The reduction in ERK1/2 and Akt phosphorylation in endothelial cells treated with Solo F-OH denotes that this compound could target the upstream components that are common to both pathways. Taken together, our results show a new and interesting biological activity of Solo F-OH as an inhibitor of the persistent and deregulated angiogenesis that characterizes cancer and other pathologies.

Isolation and Antitumoral Effect of a New Siphonochilone Derivative from African Ginger.

A new eusdesmane sesquiterpenoid, characterized as 3,5,8a-trimethyl-8-oxo-4,4a,5,6,7,8,8a,9-octahydronaphtho[2,3-b]furan-5-yl acetate (1), has been isolated from the rhizomes of the South African variety of wild ginger (Siphonochilus aethiopicus (Schweinf) B. L. Burtt). The compound was obtained by silica gel column chromatography. Its structure was elucidated by nuclear magnetic resonance spectroscopy (NMR) and mass-spectrometric (MS) analyses, including 1D-, 2D-NMR, and HR-LCMS. We also investigated the cytotoxic effect of 1 on a panel of cancer cell lines, human breast, pancreas, lung, colon, and central nervous system cancer lines. The data are not encouraging since its antitumor effect is poor. Nonetheless, the discovery of new molecules may provide a source of new compounds with important biological effects applicable to the field of medicine.

Diastereoselective C-alkylation of aldimines, derived from chiral α-carbon heteroatom-substituted aldehydes, with triethylborane. Application to the synthesis of benzylisoquinolines.

The one-pot reaction of a chiral aldehyde, p-methoxyaniline or p-fluoroaniline, and triethylborane produces the corresponding alkylated chiral amine with high yields and diastereoisomeric ratios. Stereocontrol is induced by the presence of a heteroatom in the α-position to the aldehyde. In the case of alkylation of imines derived from chiral aliphatic amines, good yields and moderate to high diastereoselectivity are obtained: yields are significantly better when the preformed imine is used in the reaction with triethyl borane, and diastereoselectivity of the reactions largely depends on the structure of the chiral aliphatic amine. The methodology is successfully applied to the synthesis of romneine, a natural benzylisoquinoline.

Green Synthesis of Silver Nanoparticles and Its Combination with Pyropia columbina (Rhodophyta) Extracts for a Cosmeceutical Application.

We report the green synthesis of silver nanoparticles (AgNPs) by using daisy petals (Bellis perennis), leek (Allium porrum) and garlic skin (Allium sativum) as reducing agents and water as solvent. AgNPs are obtained with high monodispersity, spherical shapes and size ranging from 5 to 35 nm and characterized by UV-Vis and TEM techniques. The obtained yields in AgNPs are in concordance with the total phenolic content of each plant. We also study the incorporation of AgNPs in combination with the red algae Pyropia columbina extracts (PCE) into cosmetic formulations and analyze their combined effect as photoprotective agents. Moreover, we carry out the inclusion of the PCE containing mycosporine-like amino acids (MAAs), which are strong UV-absorbing and antioxidant compounds, into ß-cyclodextrin (ßCD) and pNIPAM nanoparticles and analyze stability and release. The thermoresponsive polymer is grown by free radical polymerization using N-isopropylacrylamide (NIPAM) as the monomer, N,N'-methylenebisacrylamide (BIS) as the cross-linker, and 2,2'-azobis(2-methylpropionamidene) (V50) as the initiator, while ßCD complex is prepared by heating in water. We evaluate the nanoparticle and ßCD complex formation by UV-Vis and FT-IR, and NMR spectroscopies, respectively, and the nanoparticles' morphology, including particle size, by TEM. The cosmetic formulations are subsequently subjected to accelerated stability tests and photoprotective analyses: a synergistic effect in the combination of AgNPs and PCE in photoprotection was found. It is not related to a UV screen effect but to the antioxidant activity, having potential against photoaging.

Synthesis of new mannosyl, galactosyl and glucosyl theophylline nucleosides with potential activity as antagonists of adenosine receptors. DEMA-induced cyclization of glycosylideneiminouracils.

The synthesis of D-mannosyl, D-galactosyl and D-glucosyl theophylline nucleosides by diethoxymethyl acetate (DEMA)-induced cyclization of 4-amino-5-glycosylideneimino-1,3-dimethyluracil is reported. 8-Methyltheophylline derivatives of the same sugars were also prepared by Ac(2)O/H(+)-induced cyclization of their imine precursors. This approach has allowed beta-D-mannopyranosyl-, alpha-D-galactofuranosyl- and beta-D-glucofuranosyltheophylline nucleosides to be synthesized for the first time. The inhibition of specific binding at A(1), A(2A), A(2B) and A(3) adenosine receptors in the mannose derivatives is also reported.

Membrane surface functionalization via theophylline derivative coating and streptavidin immobilization.

Poly(vinylidene fluoride) (PVDF) and regenerated cellulose (RC) membranes were surface-modified by the adsorption of one adenosine receptor antagonist: the theophylline-oligo(ethylene glycol)-alkene derivative, Theo1. Surface modification was carried out by immersion of the membrane in a dichloromethane solution of Theo1 (PVDF+Theo1 and RC+Theo1 samples). Membrane surfaces with partial coverage by theophylline and/or its inclusion in the membrane structures were studied by X-ray photoelectron spectroscopy (XPS), solid-state nuclear magnetic resonance (SNMR), impedance spectroscopy (IS) and contact angle (CA) measurements. The Theo1 orientation was inferred from the data. Streptavidin (SA) was immobilized onto the membrane/Theo1 hybrid material. The protein-theophylline Theo1 interaction was visualized with bright field microscopy (BFM).

Functionalized lipid nanoparticles-cellophane hybrid films for molecular delivery: preparation, physicochemical characterization, and stability.

Lipid nanoparticles functionalized with the sunscreen 2,4-dihydroxybenzophenone (FLNPs) have been prepared by the ultrasound method and embedded in highly hydrophilic cellophane supports (regenerated cellulose, RC), creating biocompatible hybrid films (RC-FLNPs samples). The morphology of the FLNPs was studied with transmission microscopy, whereas the surface and interior chemical composition was analyzed by micro-Raman spectroscopy. RC-FLNPs hybrid films were prepared from the immersion of two cellophane supports with different thicknesses and water uptake properties (RC-3 and RC-6) in an aqueous dispersion of FLNPs. The structure of this hybrid material was visualized with bright-field microscopy, which clearly showed the inclusion of the FLNPs in the cellophane matrix. The stability of the RC-FLNPs films with respect to both aqueous environments and time was demonstrated by NaCl diffusion measurements. The reduction in the diffusion coefficient through the nanoparticle-modified films compared with the original supports confirms the presence of nanoparticles for concentration gradients of up to 0.4 M (osmotic pressure around 10 bar), indicating the stability of the hybrid hydrophilic material, even in aqueous environments and under matter flow conditions for a period of 21 days.

Highly stable, protein resistant thin films on SiC-modified silicon substrates.

Thin films terminated with oligo(ethylene glycol) (OEG) could be photochemically grafted onto ultrathin silicon carbide layers that were generated on silicon substrates via carbonization with acetylene at 820 degrees C. The OEG coating reduced the non-specific adsorption of fibrinogen on the substrates by 99.5% and remained resistant after storage in PBS for 4 weeks at 37 degrees C.