Synthesis and evaluation of pharmacological properties of some new xanthone derivatives with piperazine moiety

A series of new xanthone derivatives with piperazine moiety [1–7] was synthesized and evaluated for their pharmacological properties. They were subject to binding assays for α₁ and β₁ adrenergic as well as 5-HT_1A, 5-HT₆ and 5-HT_7b serotoninergic receptors. Five of the tested compounds were also evaluated for their anticonvulsant properties. The compound 3a 3-methoxy-5-{[4-(2-methoxyphenyl)piperazin-1-yl]methyl}-9H-xanthen-9-one hydrochloride exhibited significantly higher affinity for serotoninergic 5-HT_1A receptors (K_i = 24 nM) than other substances. In terms of anticonvulsant activity, 6-methoxy-2-{[4-(benzyl)piperazin-1-yl]methyl}-9H-xanthen-9-one (5) proved best properties. Its ED₅₀ determined in maximal electroshock (MES) seizure assay was 105 mg/kg b.w. (rats, p.o.). Combining of xanthone with piperazine moiety resulted in obtaining of compounds with increased bioavailability after oral administration.     

1,4-Diaryl-substituted triazoles as cyclooxygenase-2 inhibitors: Synthesis,biological evaluation and molecular modeling studies

A novel group of 1,4-diaryl-substituted triazoles was designed and synthesized by introducing the cyclooxygenase-2 (COX-2) pharmacophore SO₂NH₂ attached to one aryl ring and various substituents (H, F, Cl, CH₃ or OCH₃) attached to the other aryl ring. The effects of size and flexibility of the compounds upon COX-1/COX-2 inhibitory potency and selectivity was studied by increasing the size of an alkyl linker chain [(–CH₂)_n, where n = 0, 1, 2]. In vitro COX-1/COX-2 inhibition studies showed that all compounds (14–18, 21–25 and 28–32) are more potent inhibitors of COX-2 isozyme (IC₅₀ = 0.17–28.0 μM range) compared to COX-1 isozyme (IC₅₀ = 21.0 to >100 μM range). Within the group of 1,4 diaryl-substituted triazoles, 4-{2-[4-(4-chloro-phenyl)-[1,2,3]triazol-1-yl]-ethyl}-benzenesulfonamide (compound 30) displayed highest COX-2 inhibitory potency and selectivity (COX-1: IC₅₀ = >100 μM, COX-2: IC₅₀ = 0.17 μM, SI >588). Molecular docking studies using the catalytic site of COX-1 and COX-2, respectively, provided complementary theoretical support for the obtained experimental biological structure–activity relationship data. Results of molecular docking studies revealed that COX-2 pharmacophore SO₂NH₂ in compound 30 is positioned in the secondary pocket of COX-2 active site; with the nitrogen atom of the SO₂NH₂ group being hydrogen bonded to Q192 (N?OC = 2.85 Å), and one of the oxygen atoms of SO₂NH₂ group forming a hydrogen bond to H90 (SO?N = 2.38 Å).     

Bioactive compounds from Stuhlmannia moavi from the Madagascar dry forest

Bioassay-directed fractionation of the leaf and root extracts of the antiproliferative Madagascar plant Stuhlmannia moavi afforded 6-acetyl-5,8-dihydroxy-2-methoxy-7-methyl-1,4-naphthoquinone (stuhlmoavin, 1) as the most active compound, with an IC₅₀ value of 8.1 μM against the A2780 human ovarian cancer cell line, as well as the known homoisoflavonoid bonducellin (2) and the stilbenoids 3,4,5′-trihydroxy-3′-methoxy-trans-stilbene (3), piceatannol (4), resveratrol (5), rhapontigenin (6), and isorhapontigenin (7). The structure elucidation of all compounds was based on NMR and mass spectroscopic data, and the structure of 1 was confirmed by a single crystal X-ray analysis. Compounds 2?5 showed weak A2780 activities, with IC₅₀ values of 10.6, 54.0, 41.0, and 74.0 μM, respectively. Compounds 1?3 also showed weak antimalarial activity against Plasmodium falciparum with IC₅₀ values of 23, 26, and 27 μM, respectively.     

The Contribution of Arabidopsis Homologs of L-Gulono-1,4-lactone Oxidase to the Biosynthesis of Ascorbic Acid

To clarify the involvement of seven Arabidopsis homologs of rat L-gulono-1,4-lactone (L-GulL) oxidase, AtGulLOs, in the biosynthesis of L-ascorbic acid (AsA), transgenic tobacco cells overexpressing the various AtGulLOs were generated. Under treatment with L-GulL, the levels of total AsA in three transgenic tobacco cell lines, overexpressing AtGulLO2, 3, or 5, were significantly increased as compared with those in control cells.     

Inhibitory Activity of (9R,10S,12Z)-9,10-Dihydroxy-8-oxo-octadecenoic Acid,Its C-9 Epimer and Their Derivatives toward the Growth of Tea Pollen Tubes

The inhibitory activity of (9R,10S,12Z)-9,10-dihydroxy-8-oxooctadecenoic acid and its diacetate, acetonide and methyl ester toward tea pollen tube growth were different, the inhibition by the diacetate being the strongest. Each compound of the fatty acid and its derivatives exhibited more inhibition than its C-9 epimer. The fatty acid and its C-9 epimer showed the same toxicity against HeLa cells.     

Conversion of L-Galactono-1,4-lactone to L-Ascorbate Is Regulated by the Photosynthetic Electron Transport Chain in Arabidopsis

In this study we focused on the effects of light irradiation and the addition of L-galactono-1,4-lactone (L-GalL) on the conversion of exogenous L-GalL to L-ascorbate (AsA) and the total AsA pool size in detached leaves of Arabidopsis plants and transgenic plants expressing the rat L-gulono-1,4-lactone oxidase gene. Increases in the total AsA level in L-GalL-treated leaves depended entirely on light irradiation. Treatment with an inhibitor of photosynthetic electron transport together with L-GalL reduced the increase in total AsA under light. Light, particularly the redox state of photosynthetic electron transport, appeared to play an important role in the regulation of the conversion of L-GalL to AsA in the mitochondria, reflecting the cellular level of AsA in plants.     

Intense Chiral Optical Phenomena in Racemic Polymers by Cocrystallization With Chiral Guest Molecules: A Brief Overview

This review is devoted to the chiral optical behavior of films of racemic polymers whose chirality is induced by cocrystallization with nonracemic (also temporary) guest molecules. We provide examples of macromolecular amplification of chirality, produced by molecular and supramolecular mechanisms, on industrially relevant polymers like poly(2,6‐dimethyl‐1,4‐phenylene)oxide (PPO) and syndiotactic polystyrene (s‐PS). Chirality 28:29–38, 2016. © 2015 Wiley Periodicals, Inc.     

The aspartimide problem persists: Fluorenylmethyloxycarbonyl‐solid‐phase peptide synthesis (Fmoc‐SPPS) chain termination due to formation of N‐terminal piperazine‐2,5‐diones

Aspartimide (Asi) formation is a notorious side reaction in peptide synthesis that is well characterized and described in literature. In this context, we observed significant amounts of chain termination in Fmoc‐SPPS while synthesizing the N‐terminal Xaa‐Asp‐Yaa motif. This termination was caused by the formation of piperazine‐2,5‐diones. We investigated this side reaction using a linear model peptide and independently synthesizing its piperazine‐2,5‐dione derivative. Nuclear magnetic resonance (NMR) data of the side product present in the crude linear peptide proves that exclusively the six‐membered ring is formed whereas the theoretically conceivable seven‐membered 1,4‐diazepine‐2,5‐dione is not found. We propose a mechanism where nucleophilic attack of the N‐terminal amino function takes place at the α‐carbon of the carbonyl group of the corresponding Asi intermediate. In addition, we systematically investigated the impact of (a) different adjacent amino acid residues, (b) backbone protection, and (c) side chain protection of flanking amino acids. The side reaction is directly related to the Asi intermediate. Hence, hindering or avoiding Asi formation reduces or completely suppresses this side reaction.     

Structural and functional characterization of galactooligosaccharides in Nostoc commune: beta-D-galactofuranosyl-(1-->6)-[beta-D-galactofuranosyl-(1-->6)]2-beta-D-1,4-anhydrogalactitol and beta-(1-->6)-galactofuranosylated homologues

A new class of galactooligosaccharides has been identified from the terrestrial cyanobacterium Nostoc commune by MS and NMR techniques. These consist of beta-D-galactofuranosyl-(1-->6)-[beta-D-galactofuranosyl-(1-->6)]n-beta-d-1,4-anhydrogalactitols with n ranging from 2 to 8, corresponding to compounds designated 1 through 7. In total these saccharides amounted to approximately 0.35% of the dry thallus of N. commune, while in several other cyanobacteria they were not detected. Possibly they play some role in protection from damage by heat and desiccation as suggested by experiments with heterologous systems. For example, phosphoglucomutase (EC 2.7.5.1) from rabbit muscle was protected against heat inactivation by these oligosaccharides, and alpha-amylase (EC 3.2.1.1) from porcine pancreas by the oligosaccharides 6 and 7. The homologues of lower molecular mass, however, enhanced heat sensitivity of alpha-amylase. The viability of Escherichia coli was completely abolished by desiccation, whereas in the presence of 4 survival rates were approximately 50% of controls not subjected to desiccation. The newly identified saccharides are compared with known galactofuranose-based oligo- and polysaccharides and possible biological functions of them are discussed.