Andrea Defant

Antibacterial Polyketides from the Marine Alga-Derived Endophitic Streptomyces sundarbansensis: A Study on Hydroxypyrone Tautomerism

Polyketide 13 [=2-hydroxy-5-((6-hydroxy-4-oxo-4H-pyran-2-yl)methyl)-2-propylchroman-4-one] and three related known compounds 7, 9 and 11 were obtained and structurally characterized from Streptomyces sundarbansensis strain, an endophytic actinomycete isolated from the Algerian marine brown algae Fucus sp. Compound 13 was obtained as the major metabolite from optimized culture conditions, by using Agar state fermentation. Due to tautomeric equilibrium, 13 in CD3OD solution was able to incorporate five deuterium atoms, as deduced by NMR and ESI-MS/MS analysis. The 2-hydroxy-γ-pyrone form was established for these metabolites based on the comparison of their experimental IR spectra with the DFT calculated ones, for both the corresponding 4-hydroxy-α-pyrone and 2-hydroxy-γ-pyrone forms. During antibacterial evaluation, compound 13 stood out as the most active of the series, showing a selective activity against the gram positive pathogenic methicillin-resistant S. aureus (MRSA, MIC = 6 μΜ), with a bacteriostatic effect.

Synthesis of marine natural products with antimalarial activity.

The role played by synthetic organic chemistry of marine metabolites as potential leads for drug discovery of antimalarial agents is discussed. Syntheses of the most promising molecules are summarized, with emphasis on structure-activity relationship (SAR) studies and their mechanism of action.

A study of resveratrol‐copper complexes by electrospray ionization mass spectrometry and density functional theory calculations

Resveratrol is a polyphenolic compound found in plants and human foods which has shown biological activities including chemoprevention, acting through a mechanism which involves the reduction of Cu(II) species. By electrospray ionization (ESI) mass spectrometry we have produced and detected the resveratrol-copper complexes [Resv+Cu](+), [Resv+Cu+H(2)O](+) and [2Resv+Cu](+) by using a resveratrol/CuSO(4) solution in CH(3)CN/H(2)O. The most stable structures of the detected complexes have been calculated at the B3LYP/6-311G(d) level of theory. Resveratrol interacts with the copper ion through nucleophilic carbon atoms on the aromatic ring and the alkenyl group. The fact that only singly charged ions were observed implies that Cu(II) is reduced to Cu(I) in the ESI process. For investigating the structure-reactivity correlation, we have carried out a similar study on the synthetic analogue dihydroresveratrol (DHResv). For the latter only the [DHResv+Cu](+) complex has been detected.

Polar Metabolites of the Tropical Green SeaweedCaulerpa taxifolia Which Is Spreading in the Mediterranean Sea: Glycoglycerolipids and Stable Enols (α\=Keto Esters)

Examination of the polar components of the green seaweed Caulerpa taxifolia (Vahl) C. Agardh, which is heavily spreading in the northeastern Mediterranean, led to two families of compounds. The new (2R)-3-O-β-D-galactopyranosyl-1-O-[(7Z,10Z,13Z)-hexadeca-7,10,13-trienoyl]-2-O-[(9Z,12Z,15Z)-octadeca-1,12,15-trienoyl]-sn-glycerol (2) was isolated in low abundance, like the analogues 1 and 3 already known from freshwater cyanobacteria. The acyl positions in 1 – 3 were determined by enzymatic methods and the absolute configuration from the O-galactosylglycerol obtained upon alcaline methanolysis. More abundant were the (4-hydroxyphenyl)- and (3,4-dihydroxyphenyl)pyruvic acid methyl esters, occurring in the enol (Z) forms 13a and 14a accompanied by very minor (E) forms 13b and 14b. The latter became predominant on UV irradiation of 13a or 14a, allowing the determination of the C=C configuration of these isolatable, stable enols from 1H,13C NMR couplings (larger H−C(3)/C(1) coupling constant in the (E) than in the (Z) isomer). Contrary to literature implications, the O-galactosylglycerolipids 1 – 3 lack any cholinergic or histaminergic activity; similarly, enols (= α-keto esters) 13 and 14 or terpenoids of this seaweed were also devoid of such biological activities (see Table).

Design, Synthesis, and Biological Evaluation of Novel 2H-Pyran-2-one Derivatives as Potential HIV-1 Reverse Transcriptase Inhibitors

In search for more effective drugs against HIV infection acting as non‐nucleoside reverse transcriptase inhibitors (NNRTIs), a series of new molecules with hybrid structures based on the natural product (+)‐calanolide A and the synthetic molecule α‐APA, known as potent and selective inhibitors of this enzyme, were selected by docking calculations. A convergent synthetic strategy gave 21 compounds with a 2H‐pyran‐2‐one structural unit and bearing isosteric modifications, which were tested against HIV‐infected CEM cell cultures. Only compound 6 (4‐((2‐(1H‐indol‐3‐yl)ethyl)amino)‐6‐methyl‐2H‐pyran‐2‐one) displayed inhibitory activity (EC50: 25–50 µM). However, it was associated with a relatively high cytostatic effect on human T lymphocyte (CEM) cell cultures, not easily predictable, neither by the chemical structure nor by the computational approach. Although this drug design has failed in selecting a novel scaffold for NNRTIs, the results have driven the interest towards new potential antitumor molecules showing activity against L1210 murine leukemia and HeLa cervix carcinoma cells, among which compound 21 (6‐methyl‐4‐((2‐(naphthalen‐1‐yl)ethyl)sulfonyl)‐2H‐pyran‐2‐one) was the most effective (IC50: 0.95 and 2.9 µM, respectively).

Microwave-Assisted Multicomponent Synthesis of Aza-, Diaza-, Benzo-, and Dibenzofluorenedione Derivatives

Abstract A microwave procedure was efficiently applied to the synthesis of a series of heteropolycyclic compounds with known or potential biological activities. Antitumor amide 3was obtained in a few minutes and with high yields through a solventless, one-pot cyclization, followed by treatment with the suitable amine. This method was also used to access tetracyclic aza-compounds 5/6, where their selective formation as N,N-syn and N,N-anti regioisomers was investigated under a solventless condition, or by changing the solvent, in the presence of solid supports and a catalytic amount of ecofriendly metal salts. Thermal access to similar polycyclic compounds recently reported under conventional heating by using the preformed pyridinium or isoquinolinium ylides was improved in this instance by microwave irradiation and extended to the synthesis of diaza-esters. In any case, the one-pot, three-component cyclization was more atom-efficient than the N-ylide sequence.

An efficient route towards a new branched tetrahydrofurane δ-sugar amino acid from a pyrolysis product of cellulose

Abstract(1R,5S)-1-Hydroxy-3,6-dioxa-bicyclo[3.2.1]octan-2-one, is a bicyclic lactone obtained in gram-scale by catalytic pyrolysis of the renewable source cellulose. Now it has been used as a chiral building block in the preparation of the new δ-sugar amino acid, (3R,5S)-5-(aminoethyl)-3-hydroxytetrahydrofurane-3-carboxylic acid, by an efficient synthesis in five steps with a 67% overall yield. The structure of this tetrahydrofurane amino acid, isolated in protonated form, was assigned by extensive mono- and bidimensional 1H- and 13C-NMR analysis and mass spectrometry, including measurements by electrospray and matrix-assisted laser desorption ionization techniques, the latter one for high-resolution experiments. This amino acid is an isoster of dipeptide glycine-alanine (H-Gly-Ala-OH), with a potential use in the access of new peptidomimetics with conformationally restricted structures due to the presence of tetrahydrofurane ring. As a preliminary study in order to disclose this effect, density functional theory calculation performed in water using polar continuum model was applied to the new amino acid and H-Gly-Ala-OH dipeptide, so that to evaluate and compare the relative torsional angles for the energy-minimized structures.

Fatty acid composition of common barbel (Barbus barbus) roe and evaluation of its haemolytic and cytotoxic activities

Eggs of the common barbel (Barbus barbus) cause intoxication in humans after ingestion. In this work, the chemical composition of the haemolytically active fraction from methanolic barbel roe extract was analyzed. Compounds showing haemolytic activity and cytotoxicity towards normal and transformed cell lines were isolated and identified as polyunsaturated fatty acids, using online liquid chromatography-electrospray ionization mass spectrometry through tandem fragmentation experiments (HPLC-MS/MS). Arachidonic acid (C20:4), docosahexaenoic acid (C22:6) and eicosapentaenoic acid (C20:5) proved to be the three most abundant members of a complex series of free fatty acids ranging from C14:0 to C24:5.

Synthesis and In-Vitro Cytotoxicity Evaluation of Novel Naphtindolizinedione Derivatives, Part II: Improved Activity for Aza-Analogues

Our previous investigation on potential antitumor agents now got enriched by the evaluation of in‐vitro activity against a full panel of NCI cancer cell lines for five new compounds. The concurrent presence in the molecular structure of a nitrogen atom in the aromatic system and a N,N‐dimethylaminoethyl amide chain play a decisive role to enhance cytotoxicity. The N,N‐anti compound 14 shows a higher activity than its N,N‐syn isomer, exhibiting the best selective inhibition against the melanoma MALME‐3M cell line, with a GI50‐value (= 30 nM) corresponding to a 330‐fold increase in activity compared to the corresponding deaza‐analogue. Compound 14 is efficiently synthesized by aminolysis of the ester obtained as a single regio‐isomer by an one‐pot three‐component procedure involving metal‐assisted cyclization under microwave irradiation conditions.

Bioactive Poly(Arsenic) Compounds

An overview of the biological activities of arsenic compounds containing more than one arsenic atom in their molecular structure is presented. This contribution covers the literature of the last 10-12 years concerning the in vitro and in vivo studies on arsenic species. They include inorganic oxides and sulfides, already employed for a long time in traditional Chinese medicine and currently investigated against hematological or solid malignancies, with arsenic trioxide clinically used in the treatment of acute promyelocytic leukemia. Chemical and biological aspects on the marine product arsenicin A, representing the first and only organic polyarsenical isolated from Nature, have also been reviewed, pointing out the characterization of its C3H6As4O3 molecular structure by experimental and theoretical vibrational spectroscopies, the potent antimicrobial activities, and the promising perspectives as an antitumor agent.