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Type II diabetes mellitus (T2DM) is characterized by the presence of amyloid deposits of the human islet amyloid polypeptide (hIAPP) in pancreatic beta-cells. A wealth of data supports the hypothesis that hIAPP's toxicity is related to an abnormal interaction of amyloids with islet cell membranes. Thus, many studies aimed at finding effective therapies for T2DM focus on the design of molecules that are able to inhibit hIAPP's amyloid growth and the related membrane damage as well. Based on this view and inspired by its known anti-amyloid properties, we have functionalized resveratrol with a phosphoryl moiety (4'-O-PR) that improves its solubility and pharmacological properties. A second resveratrol derivative has also been obtained by conjugating resveratrol with a dimyristoylphosphatidyl moiety (4'-DMPR). The use of both compounds resulted in abolishing both amyloid growth and amyloid mediated POPC/POPS membrane damage in tube tests. We propose that a mixture of a water-soluble anti-aggregating compound and its lipid-anchored derivative may be employed as a general strategy to prevent and/or to halt amyloid related membrane damage.

Resveratrol, a polyphenol present in grapes and other edible plants, possesses several important pharmacological activities, including anticancer activity. Nevertheless, its therapeutic use is still limited because of some unfavourable physicochemical and pharmacokinetic properties, mainly, poor cellular uptake and too rapid metabolism resulting in elimination from the body. To meet these drawbacks, some resveratrol conjugates would be useful, which would possess improved stability, uptake and bioavailability than the lead compound, and the ability to release it once it is internalized into the cell. In this paper we report a synthetic strategy which allowed us to obtain new amphiphilic resveratrol derivatives starting from different selectively protected resveratrol phosphoramidites or even from the resveratrol triphosphoramidite. Specifically, resveratrol was conjugated through phosphate bridge(s) to different lipophilic groups related to membrane lipids, such as cholesteryl or diacylglycero moieties. All the new lipoconjugates were tested towards human neuroblastoma SH-SY5Y cells and proved to be significantly more active than resveratrol, with a concentration-dependent activity.

On the basis of a preliminary screening of seven different samples of Sicilian grape pomace, the ‘Nerello Mascalese’ sample NM2 was selected for an ethanol preparative extraction. The defatted NM2 EtOH extract was subjected to DPPH and GAE assays, showing good radical scavenging activity (SC50 = 9.9 μg/mL) and a GAE value of 397.7 mg/g extract. HPLC–DAD analysis of NM2 extract allowed a quantitative determination of the main anthocyanins (AN) and flavonols/flavonol glycosides (FL/FG). Aliquots of the NM2 extract were subjected to three different fractionation protocols (FP1, FP2 and FP3). The fractions were examined by DPPH and GAE assays, and subjected to HPLC–DAD analysis for the quantitative determination of the main AN and FL/FG. FP3 allowed obtaining a polyphenol-enriched fraction with SC50 = 14.8 μg/mL and GAE = 184.1 mg/g of fraction, accounting for only 1.3% in weight of the EtOH extract. Some considerations about the relationship between antioxidant activity and AN/FL/FG HPLC–DAD profiles are also reported.

There are differences in the allele frequency of MTHFR polymorphism between Western and African population. The aim of this study is to determinate the prevalence of MTHFR C677T and A1298C polymorphisms in young and old people living in different areas from Mediterranean to sub-Saharan areas. The observed vs expected genotype frequencies of 677T were in Hardy Weinberg equilibrium, with the exception of old Sardinian subjects (P=0.02). Calculation of 677T allele frequency in young and old African subjects (8% and 3%, respectively) indicated that the 677T allele was disadvantaged in old Africans (P=0.02). The difference among young and old Sardinians and Sicilians were not significant at the same degree (43% vs 37% P=0.07 and 46% vs 42% P=0.28, respectively). However, the reproducible trend that showed the prevalence of 677T allele in the young subjects of the three studied areas confirms the disadvantage of this polymorphism with the age. There was a significant difference (P=0.005) on the observed vs expected frequency of 1298C homozygosity in African old subjects compared to younger ones, while the observed vs expected genotype frequencies were in equilibrium in young and old Sardinian and Sicilian subjects. The frequencies of 1298C and 1298A alleles were comparable between young and old African, Sardinian and Sicilian subjects. The lower frequency of 677T allele in old African, Sardinian and Sicilian subjects compared to young ones and the absence of TT genotype among old African subjects, should be considered as a consequence of an elevated mortality of 677T carriers.

Mono[(2R)-2,3-dihydropropyl] esters of the four 3′-nucleotides of DNA, prepared from protected nucleoside phosphoramidites and [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol, were regioselectively acylated at the C-1 hydroxyl of the glycerol moiety by a lipase-catalyzed transacylation with activated palmitic acid ester in organic solvent, giving the relevant 3′-O-lysophosphatidyl-2′-deoxynucleosides. The synthesis was also adapted for the preparation of 3′-O-lysophosphatidyl derivatives of 5′-deoxy-5-fluorouridine and 5′-deoxy-5′-(methylthio)adenosine, with the 2′-O-isomer of the latter compound also being prepared. The enhanced ability of lysophosphatidyl compounds to interact with lipid monolayers was also tested in comparison with that of the relevant free nucleosides. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

5‘-O-Lysophosphatidylnucleosides [5‘-O-(1-O-acyl-sn-glycero-3-phosphoryl)nucleosides] were obtained by a two-step chemoenzymatic synthesis. 5‘-O-(sn-Glycero-3-phosphoryl)nucleosides (5‘-GPNs) were first prepared from a phosphoramidite of 1,2-O-isopropylidene-sn-glycerol and appropriately protected nucleosides, applying the phosphoramidite methodology on the solid phase or in solution. In a following step, the regioselective acylation at the C-1 hydroxyl of the glycerol moiety of 5‘-GPNs was achieved by a lipase-catalyzed transacylation with activated fatty acid esters in organic solvent. Some deoxyribo- and ribonucleosides, as well, were converted into the corresponding lysophosphatidyl derivatives utilizing either saturated or unsaturated fatty acid esters with different length alkyl chains. The synthesis was also applied to the preparation of O-(1-O-palmitoyl-sn-glycero-3-phosphoryl) conjugates of Acyclovir and AZT, of potential pharmacological interest.

Antisense oligonucleotides are promising therapeutic agents against a variety of diseases. Effective delivery of these molecules is critical in view of their clinical application. Despite the richness of synthetic strategies addressed to the lipophilic modification of oligodeoxynucleotides (ODNs) for enhancing their pharmacokinetic behavior and trans-membrane delivery, the phosphatidyl group (1,2-di-O-acyl-sn-glycero-3-phosphoryl) has been never used as the lipophilic moiety of lipid-ODN conjugates. The present paper reports a general procedure for synthesizing 5'-phosphatidyl-ODNs. By this procedure, phosphatidyl conjugates of a VEGF antisense-ODN have been prepared, which differ in the fatty acid composition of their phosphatidyl moiety. These new lipid-ODN conjugates, which have been characterized on the basis of their physicochemical properties, showed an improved resistance to exonucleases and were able to lower the VEGF-mRNA expression in human SH-SY5Y neuroblastoma cells more effectively than the relevant free antisense-ODN did.

The hydrosoluble resveratrol derivative 3-O-phosphorylresveratrol was shown to be more cytotoxic against DU 145 prostate cancer cells than its analog 4'-O-phosphorylresveratrol. In an attempt to unveil the molecular determinants that lye at the root of their different biological effects, here we investigate the interactions of the two resveratrol derivatives with DMPC model membranes by using DSC, membrane permeation/poration assays and molecular dynamics. The results show that the 3-O-derivative interacts with DMPC membranes and diffuses across them. The 4'-O-derivative lies preferentially onto the surface of membrane. The MD simulations provide a molecular interpretation of the experiments and highlight that, in order to maximize the apolar interactions, the 3-O-derivative is embedded in the lipid hydrophobic region. This topographical position of the 3-O resveratrol analog perturbs the liquid-crystalline order of the lipid bilayer promoting membrane curvature and partial lipid loss from the vesicle. This finding reconciles with the lowering of the enthalpy of the lipid phase transition and the ability of the molecule to diffuse across membranes. The present data contribute to explain the different biological activity of the two molecules and evidence that membrane permeability is a key requirement for effective design of resveratrol derivatives to be used for therapeutic purposes. (C) 2012 Elsevier Inc. All rights reserved.

A thermodynamic and proton NMR study has been carried out in order to characterize the behaviour of 2′-deoxyadenylyl-(3′→5′)-2′-deoxyadenosine towards the protonation. Conformational changes occurring following two protonation steps are discussed.

From the aqueous extract of the red alga Digenea simplex, seven Dragendorff-positive compounds have been isolated and their structures determined by spectral and chemical methods. The taxonomic significance of their occurrence and possible biosynthetic relationships between some of these compounds are also discussed. Two are new metabolites that have been assigned the structures (R)-3-dimethylsulfonio-2-methoxypropanoare {1} and (S)-2-acetamido-5-trimethylammoniopentanoate {2}

A weak alkaline solution of 3-hydroxykynurenine was oxidized using potassium ferricyanide. A stable epr signal was recorded, probably arising from a phenoxazine intermediate. A plausible radical mechanism for this reaction is presented.

5‘-O-Lysophosphatidylnucleosides [5‘-O-(1-O-acyl-sn-glycero-3-phosphoryl)nucleosides] were obtained by a two-step chemoenzymatic synthesis. 5‘-O-(sn-Glycero-3-phosphoryl)nucleosides (5‘-GPNs) were first prepared from a phosphoramidite of 1,2-O-isopropylidene-sn-glycerol and appropriately protected nucleosides, applying the phosphoramidite methodology on the solid phase or in solution. In a following step, the regioselective acylation at the C-1 hydroxyl of the glycerol moiety of 5‘-GPNs was achieved by a lipase-catalyzed transacylation with activated fatty acid esters in organic solvent. Some deoxyribo- and ribonucleosides, as well, were converted into the corresponding lysophosphatidyl derivatives utilizing either saturated or unsaturated fatty acid esters with different length alkyl chains. The synthesis was also applied to the preparation of O-(1-O-palmitoyl-sn-glycero-3-phosphoryl) conjugates of Acyclovir and AZT, of potential pharmacological interest.

Publisher Summary A variety of studies indicate that the regular dietary consumption of extra virgin olive oil has a protective effect towards coronary heart diseases and breast cancer. Many researchers, oriented at identifying the main protective agents of olive oil, have pointed to the antioxidative phenolic constituents. Some studies on olive phenols have highlighted the importance of the lipophilic character of the antioxidant with reference to the dispersion medium (bulk oil, emulsions), to the cell uptake and membrane crossing, and to the substrate to be protected (LDL or other cellular constituents). In addition to these data, which are of particular interest in the biomedical field, the agro-industry is undergoing new pressures due to the widespread concern about the use of synthetic additives and antioxidants and to a growing demand for safer foods and beverages. This has led to a drive, by the industries of the agro-alimentary sector, to search for new antioxidants and other nutritional supplements of natural origin or obtained by simple modification of natural products. In fact, oxidation is one of the main causes of food deterioration, especially in oils and fats. Moreover, oxidized lipids, when absorbed in mammals, are incorporated into lipoproteins and may contribute to atherosclerosis. Thus, the lipophilic HT analogues may be useful in the formulation of “beneficial foods” for the prevention and treatment of chronic pathologies associated with reactive radical damage or as additives for preserving foods from oxidation processes. On this basis, this chapter focuses on hydroxytyrosol lipophilic analogues, and in particular on their synthesis, their radical scavenging activities and other protective properties. It reviews only the recent literature and includes almost exclusively those synthetic analogues that have been submitted to antioxidant activity assays.

The relative content of (2S)- and (2R)-naringin in the albedo of pummelo during maturation in the entire season was determined by normal-phase HPLC using Chiralpak IB, a polysaccharide-derived chiral stationary phase, and n-hexane/ethanol doped with 0.5% TFA as mobile phase. A sigmoid curve was obtained showing variation from 95.3% of (2S)-naringin in very immature fruits to 53% in mature fruit samples (2.3 and 14.4cm diameter, respectively). A comparison was made with previous results obtained for grapefruit and sour orange and a tentative explanation of the bitter taste of sour orange is proposed. The Chiralpak IB is much more efficient with respect to the Chiralcel OD used for the other two Citrus species and separation and resolution factors of 1.73 and 9.2, respectively, were achieved. Authentic samples of naringin and neohesperidin were also separated into their C-2 diastereomers with Chiralpak IB and isolation of the pure diastereomers of naringin was accomplished.

The fractionation, guided by cell-growth inhibition assay, of the EtOAc crude extract from grape stems of the Sicilian Vitis vinifera variety 'Nerello Mascalese' allowed identification often constituents, isolated either as pure compounds (1, 3-5, 7-10) or inseparable mixtures (2a-d and 6a-e). The pure constituents were: two triterpenoid acids, oleanolic (1) and betulinic acids (5); daucosterol (7); a stilbenoid, E-resveratrol (3) and its dimer E-epsilon-viniferin (4); the simple phenol gallic acid (8); and the flavanols catechin (9) and gallocatechin (10). Four 6'-O-acyldaucosterols (2a-d) and five 1,2-di-O-acyl-3-O-beta-D-galactopyranosyl glycerols (6a-e) were also identified as inseparable mixtures. All the isolated compounds were subjected to spectroscopic analysis and MTT bioassay on MCF-7 human breast cancer cells. The majority showed growth-inhibitory activity, 5 being the most active (GI50 = 0.57 microM). Compounds 3-5 were also tested on HT-29, U-87-MG and U-373-MG cell lines.

The HPLC separation of the enantiomers of six phthalans (1,3-dihydrobenzo[c]furans) synthesized as racemic mixtures from ortho-lithiated aryloxiranes was accomplished in the normal-phase mode using seven polysaccharide-derived and Pirkle-type chiral stationary phases (CSPs) and n-hexane/2-propanol mixtures as mobile phases. Separation and resolution factors up to 1.6 and 4.2, respectively, were obtained. The performances of various CSPs with regard to the same compound were, however, quite different not only between the two types of CSPs but also within the same type (polysaccharide-derived or Pirkle-type). Also diastereomeric pairs of phthalans show different enantioseparation using the same CSP.

Very short chain 5'-O-lysophosphatidyloligonucleotides [5'-O-(1-O-palmitoyl-sn-glycero-3-phosphoryl)oligode-oxynucleotides, (5'-LyPOdNs)] were synthesized following a two-step chemoenzymatic synthesis. 5'-O-(sn-Glycero-3-phosphoryl)oligodeoxynucleotides (5'-GPOdNs) were first prepared by simply using a phosphoramidite of [(45)-2,2-dimethyl-l,3-dioxolan-4-yl]methanol (1) in a further coupling step after the solid-phase elongation of each desired oligodeoxynucleotide. Next, the regioselective palmitoylation at the C-1 hydroxyl of the glycerol moiety of 5'-GPOdNs was achieved by a lipase-catalyzed transacylation with trifluoroethyl palmitate in organic solvent. Despite of the molecular bulkiness of 5'-GPOdNs, 2-, 3-, and 4-mer 5'-LyPOdNs were prepared by this procedure. Although in very low yield, 5- and 6-mer 5'-LyPOdNs were also obtained by this way.

We have investigated the oxidative behavior of sterols such as cholesteryl acetate ( 1 ), 7-dehydrocholesteryl acetate ( 2 ), ergosteryl acetate ( 3 ), cholecalciferol acetate (Vitamin D 3 acetate) ( 4 ) and ergocalciferol acetate (Vitamin D 2 acetate) ( 5 ) with the oxidant system methyltrioxorhenium/H 2 O 2 /pyridine in order to check potential parameters controlling the selectivity. The reactions, performed in CH 2 Cl 2 /H 2 O at 25 °C, have shown good regio- and stereoselectivity. All oxidation products were isolated by high-performance liquid chromatography (HPLC) and characterized by MS(EI) or FAB, 1 H NMR, 13 C NMR, APT, COSY, HSQC, HMBC, ROESY and NOEDS measurements. Seven new oxygenated compounds were also obtained. Under the experimental conditions adopted in this work, only the diene steroids, i.e. 7-dehydrocholesteryl acetate and ergosteryl acetate, undergo hydrolytic oxirane ring opening, whereas Vitamin D 2 and D 3 acetates, containing the triene system and cholesteryl acetate yield only epoxides. The selectivity seems to be controlled by the nucleophilicity of double bonds and by stereoelectronic and steric effects.

Low levels of plasma homocysteine have been found in children and adult populations living in Burkina Faso in association with a low prevalence of coronary heart disease.Based on this finding, the levels of plasma homocysteine and other thiols (cysteine, cysteinylglycine, glutathione) in postmenopausal women living in Burkina Faso were evaluated with the aim of investigating whether age and life conditions influence plasma homocysteine and other thiol levels.It was found that in older postmenopausal women the mean level of homocysteine was higher (16.4+/-6.6 micromol/L) than in fertile women (6.8+/-1.2 micromol/L) and that this increase was correlated with cysteine levels (166.6+/-44.6 micromol/L). While the glutathione level in postmenopausal women was lower (3.6+/-2.3 micromol/L) compared with fertile women (7.0+/-1.7 micromol/L), cysteinylglycine levels were within the normal range (29.9+/-9.3 micromol/L). No correlation was found between homocysteine levels and serum folate, vitamin B(12), vitamin B(6), cystatin C and serum creatinine levels. The older the women were, the higher were their plasma homocysteine levels: levels up to 20.2+/-9.1 micromol/L were found in those70 years old.The elevated levels of homocysteine in the postmenopausal women of Burkina Faso must be viewed as a characteristic of older age and its metabolic consequences.

Background : Plasmodium falciparum utilises the polyamine pathway, essential in proliferation and differentiation, and imposes an oxidative stress on host cell, enhancing the loss of glutathione. Methods : Standard hematological parameters were determined in 40 black African subjects with acute P. falciparum malaria, 30 aged 5–24 months, 5 aged 4–10 years and 5 aged 19–35 years. Plasma homocysteine, cysteine, glutathione and cysteinylglycine levels were measured by HPLC method. Twenty-eight healthy black children (15 aged 6–24 months and 13 aged 3–10 years) and 20 healthy black adults (aged 20–40 years) were also included as controls. Results : Plasma homocysteine levels were higher in all subjects with P. falciparum malaria and correlated positively with the disease severity and number of parasites, but negatively with Hb levels and patient ages. Cysteine level was found higher in all patients and markedly higher in 4–10 year old patients. Cysteinylglycine level was found lower particularly in 19–35 year old patients. Glutathione level was significantly lower in all patients. Conclusions : The elevated level of homocysteine during acute P. falciparum infection suggests an imbalance in the folate cycle, which could be a consequence of the reduced availability of NADPH and Vit B 12 , caused by increased oxidative stress. This may suggest a selection for the C677T MTHFR allele, driven by P. falciparum in sub-Saharan regions. Hence Hcy level could be useful as a predictive parameter of severity, as well as of treatment efficacy.

Background: Low circulating plasma levels of total homocysteine (tHcy) are associated with a lower prevalence of coronary heart disease among black people than among white people living in Burkina Faso. Objective: The purpose of this study was to provide a rationale for a possible mechanism for the decrease in plasma tHcy levels among black people compared with white people living in Burkina Faso. Methods: Healthy, black, adult, lifelong inhabitants of Burkina Faso and healthy, white adults born in Italy but living in Burkina Faso ≥5 years were eligible for enrollment. Controlled diets were assigned to all subjects for 2 weeks before the study. After an overnight (12-hour) fast, a methionine-loading test was performed in all subjects. Plasma levels of tHcy, cysteine, glutathione, and cysteinylglycine were measured simultaneously using high-performance liquid chromatography after fasting (baseline) and at either 4 and 8 hours (n = 30) or 2, 4, 6, and 8 hours (n = 4) after methionine loading. During the 12 hours after loading, the clinical conditions and adverse events of subjects were monitored. Results were analyzed using the Student t test and Mann-Whitney U test. Results: Seventeen black adults (9 males, 8 females; median age, 21 years) and 17 white adults (8 males, 9 females; median age, 35 years) were enrolled. Mean plasma levels of tHcy, cysteine, and glutathione increased from mean baseline levels more slowly in the black group than in the white group and peaked 8 hours after methionine loading (16.8 ± 3.0 μmol/L, 130.4 ± 25.7 μmol/L, and 68.3 ± 21.2 μmol/L, respectively). In the white group, these levels peaked 4 hours after loading (16.1 ± 4.0 μmol/L, 215.8 ± 18.6 μmol/L, and 38.6 ± 12.4 μmol/L, respectively). Only the mean plasma cysteinylglycine level decreased significantly (from 35.7 ± 11.4 μmol/L to 19.0 ± 6.1 μmol/L; P Conclusions: The findings of this study suggest that, in addition to lower plasma tHcy levels, the metabolism of plasma tHcy is different in black people than in white people after methionine loading. This difference may be due to different alimentary habits associated with a reduced dietary availability of methionine. Moreover, the higher plasma levels of glutathione before and after methionine loading appear to occur exclusively in black people compared with whites and correspond with the variation of cysteinylglycine, suggesting that, in addition to nutritional factors, a racial component may contribute to the difference in plasma levels of tHcy. This difference also might explain, in part, the lower prevalence of coronary heart disease in black people living in Burkina Faso compared with that in other populations.

An oligodeoxynucleic sequence of 30 bases (30-mer ODN), complementary to a region of beta-endorphin mRNA, was synthesized to have an antisense effect with regard to the expression of this oligopeptide. Following the solid-phase synthesis of the oligodeoxynucleotide, the 30-mer ODN was encapsulated within liposomes to provide a higher resistance against DNases and an improved entrance into cells. The most suitable liposome formulation as a 30-mer ODN carrier consisted of small unilamellar vesicles (50 nm) with an encapsulation capacity of 4.76 microL/micromol. The liposomal formulations containing dipalmitoyl-DL-alpha-phosphatidyl-L-serine presented fusogenic properties, which are of great importance for the delivery of antisense compounds. The antisense activity of 30-mer ODN-loaded liposomes was evaluated by the determination of beta-endorphin levels in AtT-20 cells. The free 30-mer ODN did not provide any lowering of the beta-endorphin production, whereas the liposomally entrapped compound elicited a concentration-dependent inhibition. The inhibition was determined by a sequence-specific binding of the 30-mer ODN with the target mRNA.

The direct HPLC enantiomeric separation of five fluorenone-1,4-dihydropyridine-3,5-dicarboxylic diesters has been achieved using a Chiralpak AD stationary phase obtaining simultaneously good enantioselectivities, resolution factors, and elution times. CD spectra of the individual enantiomers for two compounds were measured. Thermodynamic parameters associated with the adsorption equilibria of the enantiomers with the chiral stationary phase were obtained from HLPC runs at various temperatures. The conformational preferences of the synperiplanar fluorenone group and of the cis/cis ester groups were obtained by 1H NMR spectra, including NOE experiments.

The fractionation, guided by cell-growth inhibition assay, of the EtOAc crude extract from grape stems of the Sicilian Vitis vinifera variety ‘Nerello Mascalese’ allowed identification of ten constituents, isolated either as pure compounds (1, 3–5, 7–10) or inseparable mixtures (2a-d and 6a-e). The pure constituents were: two triterpenoid acids, oleanolic (1) and betulinic acids (5); daucosterol (7); a stilbenoid, E-resveratrol (3) and its dimer E-ε-viniferin (4); the simple phenol gallic acid (8); and the flavanols catechin (9) and gallocatechin (10). Four 6′- O-acyldaucosterols (2a-d) and five 1,2-di- O-acyl-3- O-β-D-galactopyranosyl glycerols (6a-e) were also identified as inseparable mixtures. All the isolated compounds were subjected to spectroscopic analysis and MTT bioassay on MCF-7 human breast cancer cells. The majority showed growth-inhibitory activity, 5 being the most active (GI50 = 0.57 μM). Compounds 3–5 were also tested on HT-29, U-87-MG and U-373-MG cell lines.

A weak alkaline solution of 3-hydroxykynurenine was oxidized using potassium ferricyanide. A stable epr signal was recorded, probably arising from a phenoxazine intermediate. A plausible radical mechanism for this reaction is presented.

The distribution of Dragendorff-positive compounds in more than 20 species of Mediterranean red algae has been investigated. In addition to several new occurrences of known metabolites, two previously unreported compounds, N -acetyllaminine; and N , N -dimethyl-methionine sulphoxide, have been isolated and their structures have been assigned mainly on the basis of spectral data. The possible taxonomic significance of onium salts is discussed.

In contrast with what seems to occur in the northwestern Mediterranean, pollution of the central Mediterranean by organochlorine compounds (mainly DDTs and PCBs), as can be assessed from their concentrations in five marine animals, did not undergo significant changes over a three-year period.

1. 1. Melanosomes from skin and liver of Rana esculenta L. have been isolated and some chemical properties of the relevant melanin and protein components were compared. 2. 2. In both cases the pigments show spectroscopic (ESR) and chemical characteristics similar to those of eumelanins. The melanin content in skin melanosomes is higher than in the liver counterparts. 3. 3. Amino acid patterns of the two protein components are different in their quantitative composition and both are characterized by high levels of glycine and proline. 4. 4. The results as a whole indicate that skin and liver melanosomes from the same animal markedly differ in their chemical composition.

A method for the determination of 2-[(N-phenyl)benzylaminomethyl]-2-imidazoline X H3PO4 (antazoline phosphate) and 2-(1,2,3,4-tetrahydro-1-naphthyl)-2-imidazoline X HCl (tetrahydrozoline hydrochloride) in ophthalmic solution is described. The pharmaceutical preparation is analysed directly by reversed-phase ion-pair high-performance liquid chromatography and the method is very rapid, selective and simple.

Levels of PCBs, DDTs and BHCs were measured in sediments taken from the central Mediterranean. BHC was usually −1 ; ΣDDT (sum of DDT, DDE and DDD) ranged from −1 to 27.5 ng g −1 ; ΣPCBs generally ranged from ca. 1 ng g −1 to > 80 ng g −1 , but exceptionally high values (130–457 ng g −1 ) were observed from stations within Augusta Harbor.

Recent literature about stilbene-based analogues of resveratrol (1) has been reviewed, and a total of 94 compounds are reported (see structures 4 – 97), selected either for their promising anti-tumor properties or as comparative terms in SAR studies. As a general outline, these recent literature data confirm the previously reported observation that minimal modification in the nature and position of the substituents on the stilbene nucleus may cause large variations in their biological activity and, more specifically, in their anti-tumor properties. Among the polyhydroxylated stilbenes, it has been established that those with either a catechol or pyrogallol moiety are far better radical scavengers than either 1 or other analogues lacking an ortho-dihydroxy group, and this property was shown to be related to pro-apoptotic activity. In the large majority of cases where couples of E- and Z-isomers were evaluated for either cytotoxic or pro-apoptotic activity, the Z-isomers were significantly more active than their E analogues; nevertheless, a general rule stating that stilbenoids with Z configuration of the double bond display a considerably higher antiproliferative activity than their E-isomers cannot be considered as established. A variety of methoxystilbenes has been reported recently: in many cases these analogues showed either potent antiproliferative and pro-apoptotic activity or strong inhibition of TNFα-induced activation of NF- kB. Globally considered, polymethoxystilbenes are a sub-group of great interest among the resveratrol analogues: these analogues appear worthy of a deeper evaluation also in connection with their potential anti-angiogenic properties. In addition, in vivo studies indicate that methoxystilbenes undergo different metabolic conversion and have a higher bioavailability than resveratrol. The potent activity of some amino- and halogenated stilbenes is undoubtedly worthy of attention, but the toxicity of these compounds to normal cells has rarely been evaluated. In conclusion, the synthesis and evaluation of stilbene-based resveratrol analogues proved to be a highly active field of research and has recently afforded compounds with either cytotoxic or pro-apoptotic activity in the nanomolar range. Nevertheless, the exact structural determinants to optimize the anti-tumor properties of these compounds and details of their mechanism of action remain to be clarified.

3- O-, 3,5-di- O- and 4′- O-phosphoryl derivatives of ( E)-resveratrol have been obtained following a chemoenzymatic strategy. Variedly acylated resveratrol derivatives have been obtained first by exploiting regioselective properties of Pseudomonas cepacea or Candida antarctica lipases in organic solvents. Each acyl-resveratrol was then phosphorylated by the phosphoramidite chemistry protocol and in sequence freed of protective groups, affording the desired O-phosphoryl derivative. Following UV-absorption spectroscopic investigation on the interaction of the newly synthesized compounds with DNA, 4′- O-phosphorylresveratrol exhibited the best binding affinity. As a result of cytotoxicity tests, 3- O-phosphorylresveratrol was more active than resveratrol against DU 145 prostate cancer cells.

The stilbenoids E-resveratrol (E-3,5,4′-trihydroxystilbene, 1), E-3,5,4′-trimethoxystilbene (2), E-3,4,4′-trimethoxystilbene (3) and E-3,4′-dimethoxy-5-hydroxystilbene (4) were converted by photoisomerization to their corresponding Z-isomers 5D8. Compounds 1D8 were subjected to antiproliferative activity bioassays towards a set of four different human cancer cell lines, namely DU-145 (androgen not responsive human prostate tumor), LNCaP (androgen responsive human prostate tumor), M-14 (human melanoma) and KB (human mouth epidermoid carcinoma). The methylated analogues of 1 are more active than the natural lead in the majority of bioassays. The most active compound was Z-3,5,4′-trimethoxystilbene (6), which showed against DU-145 and LNCaP cells GI50 values close to those of the anticancer drug vinorelbine; 6 resulted more active than its E-isomer 2 towards DU-145, LNCaP and especially KB cell lines. A number of methylated Z-isomers displayed a higher activity than their E-isomers, but E-resveratrol (1) was more active than Z-resveratrol (5) towards all the tested cell lines.

An unusual compound (−)-(S)-4-dimethylsulfonio-2-methoxybutyrate, was identified in aqueous—ethanolic extracts of the red alga Rytiphloea tinctoria.

4-Hydroxy- N -methylproline, an unusual amino acid which has been reported in only a few species of higher plants, has been identified in the aqueous extract of the red alga Chondria coerulescens . Spectral features of this compound are discussed in detail.