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In this work, two novel selenium glycoconjugates are proposed as antioxidants to accelerate skin repair. These molecules, designed with more antioxidant sites and improved healing activity, are composed by a selenosugar covalently linked to a caffeic acid or a resveratrol residue. The selenium glycoconjugates have been synthesised and then loaded in a hydrogel flexible film, in order to obtain an active wound dressing. The chemical interaction between the hydrogel and the embedded selenium glycoconjugates can be modulated by the pH values, resulting in a pH-sensitive delivery system. In particular, the caffeic acid-containing compound is released at acute wounds’ pH (7.4), while the resveratrol-containing conjugate is released at pH 9.6, typical of chronic wounds. The specific characteristics of the hydrogel and the antioxidant features of the selenium glycoconjugates, as well as the proven controlled release, candidate the designed system at wound care practices.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the loss of the cognitive functions and dementia. Several scientific evidences report that a central role in the pathogenesis of AD is played by the brain deposition of insoluble aggregates of β-amyloid protein (Aβ) proteins, thus causing neuronal cell death [1]. For this reason, one of the promising approach is to inhibit the aggregation of Aβ peptides. Because Aβ is self-assembling, one possible strategy to prevent this process is to use short peptide fragments homologous to the full-length wild-type Aβ protein. From this consideration, several short synthetic peptides were designed as beta-sheet breakers (BSB) [2]. In particular, the pentapetide Ac-LPFFD-NH2 (iAβ5p) exhibited a certain capability to inhibit Aβ fibrillogenesis [3]. iAβ5p analogs [4] were, then, designed by introducing N-Methylation at the amide bond nitrogen were also promising BSB. Here, we describe the methodological approach, which combines 3D GRID-based pharmacophore peptide screening with Well-Tempered Metadynamics simulations aimed to the discovery of novel N-Methylated BSB. This approach led us to identify two promising, cell permeable, N-Methylated peptides that were further evaluated for their BSB properties showing a significant improvement of the fibrillogenesis inhibition with respect to the lead iAβ5p.

A series of l -lysine-conjugated pyridophenoxazinones 2–5 and 2′-5′ were designed and synthesized for developing compounds with multimodal anticancer potentialities. All compounds inhibited the proliferation of a panel of human liquid and solid neoplastic cell lines. 2 and 5 were the most active compounds with IC50 values in the submicromolar range. UV–vis, 1H NMR, unwinding, and docking experiments demonstrated that they intercalate between the middle 5′-GC-3′ base pairs with the carboxamide side chain lying into major groove. Charge-transfer contribution to the complex stability, evaluated by ab initio calculations, was found to correlate with cytotoxicity. Relaxation and cleavage assays showed that 2 and 5 selectively target Topo IIα over Topo IIβ and stimulate the formation of covalent Topo II–DNA complexes, functioning as poisons. Moreover, compound 5 induced DNA damage and arrested MCF-7 cells at the G2/M phase. Altogether, the work provides interesting structure-activity relationships in the pyridophenoxazinone- l -lysine conjugate series and identifies 5 as a promising candidate for further in vivo evaluation.

Herpes simplex virus 1 (HSV-1) can infect a wide range of cell types, including cells of the adaptive and innate immunity but, normally, it completes a fully-permissive replication cycle only in epithelial or neural cells. Complex mechanisms controlling this delicate balance in immune cells and consequent restriction of HSV-1 infection in these cells have not been completely elucidated. We have recently demonstrated that the transcription factor nuclear factor kappa B (NF-&kappa, B) can act as a main permissiveness regulator of HSV-1 infection in monocytic cells, however, mediators involved in this regulation have not been identified. To better define mechanisms involved in this phenomenon and, particularly, the possible involvement of ROS, wild type U937 cells or U937 cells stably transfected with a dominant-negative (DN) I&kappa, B-mutant and selenium-containing compounds, as anti-oxidants, were utilized. The main results can be summarized as follows. HSV-1 infection induces an immediate ROS production in U937 monocytic cells that can efficiently activate NF-&kappa, B but not in DN-I&kappa, B-mutant cells. Treatment with selenium-containing antioxidants efficiently inhibited HSV-1-induced ROS generation while producing increased levels of HSV-1 replication and a reduction of HSV-1-induced NF-&kappa, B activation in U937 monocytic cells. Our results suggest a scenario in which an efficient NF-&kappa, B-dependent ROS production in response to infection could contribute in limiting HSV-1 replication in monocytes/macrophages, thus avoiding possible irreparable damage to the innate immune system of the host during HSV-1 infection.

We report the ready asymmetric synthesis of nucleoside analogues containing a 1,3-dithiolane ring that mimics the sugar moiety of natural nucleosides. The synthesis is accomplished in three main steps from benzoyloxyethanal 1,3-dithiolane, the key step being its conversion into a chiral monosulfoxide by a modified Sharpless sulfo-oxygenation reaction. The nucleoside analogues were obtained in good overall yields and with excellent enantiomeric excesses. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

In a recent paper2 we have reported the design and synthesis of 3-C-lithiated 5,6-dihydro-1,4-dithiin-2-yl[(4-methoxybenzyl)oxy]methane (1) which can be utilized as an allylic alcohol anion equivalent and leads to three-carbon elongations of various electrophiles by introduction of a fully protected hydroxypropenyl moiety. The latter contains a double bond, which can be unravelled to the cis configuration by diastereoselective removal3 of the dimethylene-disulfur bridge, as well as a protected primary hydroxyl group that, depending on the deprotection conditions used (DDQ/NaBH4 or DDQ), may either lead to the free allylic alcohol or to an α,β-unsaturated aldehyde.

A new high yielding coupling reaction of C-2 monosubstituted 5,6-dihydro-1,4-dithiins with aldehydes is reported. In this way allylic alcohols having the cis-substituted double bond tied up by a sulfur-containing ring can be readily prepared. Subsequent stereoselective sulfur removal then affords allylic alcohols with cis-configurated double bond.

Ketones are reported to be conveniently converted into their α-tolylsulfinylated derivatives. This new procedure is based on the reaction of their corresponding trimethylsilyl enol ethers with p-toluenesulfinyl p-tolylsulfone in the presence of tris(dimethylamino)sulfur trimethylsilyldifluoride (TAS-F). Considering that β-ketosulfoxides are key intermediates for the preparation of α,β-unsaturated ketones, this procedure turns out to be of rather broad synthetic relevance.

N-Acetyl-1,3-thiazolidine derivatives of cyclohexanones, when treated with a threefold excess N-bromosuccinimide in anhydrous chloroform at room temperature, smoothly afford N-acetyl-2,3-dihydro-1,4-benzothiazines. This represents the first general route to such heterocyclic system in one step from aliphatic precursors. The synthesis of optically active N-acetyl-2,3-dihydro-1,4-benzothiazines is also reported

2-[[O-(p-Methoxybenzyl)-oxy]methyl]-5,6-dihydro-1,4-dithiin 1 is a versatile three carbon homologation reagent which has been conveniently used in the synthesis of enantiomerically pure modified nucleosides.

N-Acetyl-1,3-thiazolidine derivatives of cyclohexanones, when treated with a threefold excess N-bromosuccinimide in anhydrous chloroform at room temperature, smoothly afford N-acetyl-2,3-dihydro-1,4-benzothiazines. This represents the first general route to such heterocyclic system in one step from aliphatic precursors. The synthesis of optically active N-acetyl-2,3-dihydro-1,4-benzothiazines is also reported

Perbenzylated 1,7-dioxaspiro[5,5]undec-4-ene derivatives of sugars are obtained in three steps, starting from fully protected glycono-1,5-lactones. The procedure is based on the attack of a lithiated dithiinyl reagent (6) on the starting δ-glyconolactone. The C-glycosidation leads to the sole thermodynamically more stable α-hemiacetal derivative, the spirocyclization of which is then accomplished with BF3·Et2O. The fully protected unsaturated spiroacetals can be smoothly desulfurized for the purpose of any further elaborations of the free double bond. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

A new reagent, based on a 5,6-dihydro-1,4-dithiin heterocyclic system1, has been devised and conveniently used for 3 carbon elongations of various electrophiles. In fact, it acts as either a propenyl alcohol or an acrolein anion equivalent, introducing into the new molecule a moiety consisting of fully protected double bond and allylic oxygen.