Costantino Floris

Falcarinol is a covalent cannabinoid CB1 receptor antagonist and induces pro-allergic effects in skin.

The skin irritant polyyne falcarinol (panaxynol, carotatoxin) is found in carrots, parsley, celery, and in the medicinal plant Panax ginseng. In our ongoing search for new cannabinoid (CB) receptor ligands we have isolated falcarinol from the endemic Sardinian plant Seseli praecox. We show that falcarinol exhibits binding affinity to both human CB receptors but selectively alkylates the anandamide binding site in the CB(1) receptor (K(i)=594nM), acting as covalent inverse agonist in CB(1) receptor-transfected CHO cells. Given the inherent instability of purified falcarinol we repeatedly isolated this compound for biological characterization and one new polyyne was characterized. In human HaCaT keratinocytes falcarinol increased the expression of the pro-allergic chemokines IL-8 and CCL2/MCP-1 in a CB(1) receptor-dependent manner. Moreover, falcarinol inhibited the effects of anandamide on TNF-alpha stimulated keratinocytes. In vivo, falcarinol strongly aggravated histamine-induced oedema reactions in skin prick tests. Both effects were also obtained with the CB(1) receptor inverse agonist rimonabant, thus indicating the potential role of the CB(1) receptor in skin immunopharmacology. Our data suggest anti-allergic effects of anandamide and that falcarinol-associated dermatitis is due to antagonism of the CB(1) receptor in keratinocytes, leading to increased chemokine expression and aggravation of histamine action.

Cytotoxic Phloroglucinols from the Leaves of Myrtus communis

Bioactivity-guided fractionation of a dichloromethane extract of the leaves of Myrtus communis led to the isolation of phloroglucinol derivatives. The structures of the new myrtucommulones J, K, and L (1-3) and the previously known myrtucommulone A (4) were elucidated on the basis of extensive 1D and 2D NMR experiments as well as high-resolutionmass spectrometry. Myrtucommulone J was obtained as a tautomeric pair (1/1a). The compounds were tested in vitro for their cytotoxic and antibacterial activities.

Metalation reactions. XIV. Regiospecific preparation of polysubstituted benzenes via mono- or di-lithiation reactions of aromatic thioethers☆

Abstract The preparation of polyfunctionalized aromatic thioethers either by one-step dilithiation or by two successive one-flask monometalation reactions is described. By acting on 1 two equal or different electrophiles one on the thiomethyl group and one in the ortho -position with respect to it are introduced; by acting on 11 and on 35 the substitution involves the thiomethyl carbon atom and that in the ortho -position with respect to the alkoxy group. In the case of the homologous isopropylthio (23) the substitution involves the two aryl carbon atoms in the ortho -position to both functions. In the case of the p -disubstituted isomers (49, 59) analogous behaviour to ortho isomers in one-step metalation reaction is observed, while the two hydrogen atoms in the ortho -positions to the methoxy group are substituted when two successive monometalations are employed. The metalation of 40 results low selective. The behaviour of 79 and 93 is analogous to 1, while 72, 88 and 96 undergo only one-step monometalation reactions.

Copper(II) and nickel(II) uptake from aqueous solutions by cork wastes: a NMR and potentiometric study

Due to the increasing interest in the use of biomasses from agriculture as removing agents for heavy metals in waste effluents, we present here a joint potentiometric and 13C MAS and cross polarization-magic angle spinning NMR (CP-MAS NMR) study on cork interaction with Cu(II) and Ni(II). Through potentiometry we were able to distinguish two kind of interactions, a stronger one which involves protonated sites on cork and a second that allows hydroxide precipitation of the bound metal ion into the cork structure. NMR signal analysis suggests a specific metal complexation on the carbohydrate moieties of polymeric cork matrix. The 13C MAS NMR suggests that the dynamics in the MHz range and the overall arrangement of polymeric matrix is not affected by metal binding; and the spin relaxation times T1ρ(1H) and T1ρ(13C) show that no significant difference of relaxation processes in the KHz range is introduced by metal coordination.

Topical Anti-inflammatory Activity of Flavonoids and a New Xanthone from Santolina insularis

Bioactivity-guided fractionation of the methanol extract from the leaves of Santolina insularis led to the isolation of one new xanthone, (E)-3-{6-[(E)-3-hydroxy-3-oxo-1-propenyl]-9- oxo-9H-xanthen-2-yl}-2-propenoic acid, together with six known flavonoids: hispidulin, nepetin, cirsimaritin, rhamnocitrin, luteolin and luteolin 7-O-β-ᴅ-glucopyranoside. The structures were elucidated by means of 1D-, 2D-NMR spectroscopy and mass spectrometry. The topical anti-inflammatory activity of all isolated compounds and extracts was investigated employing the croton oil-induced dermatitis in mouse ear. The most active compound, luteolin, showed an ID50 of 0.3 μmol/cm2 and prevented ear oedema more effectively than an equimolar dose of indomethacin within 24 h.

New cytotoxic saturated and unsaturated cyclohexanones from Anthemis maritima.

Two new cyclohexenones (antheminones A and B) and a new cyclohexanone, (antheminone C) along with five known compounds were isolated from the leaves of Anthemis maritima L. The structures were mainly deduced from extensive 1D and 2D NMR spectroscopy and mass spectrometry. The new compounds were tested in vitro for their cytotoxic activity against adherent and non-adherent cancer cell lines. Antheminones A and C exhibited significant antiproliferative activity against leukemia cells with IC(50) values ranging from 3.2 to 14 microM.

Phenolic constituents from Ephedra Nebrodensis

Two new phenolic glycosides, 4-hydroxy-3-(3-methyl-2-butenyl)phenyl β-D-glucopyranoside (nebrodenside A) and O-coumaric acid β-D-allopyranoside (nebrodenside B), were isolated from the aerial parts of Ephedra nebrodensis. In addition, O-coumaric acid glucoside, (−)-epicatechin, and (−)-ephedrine were also isolated. The structures were deduced from extensive 1D and 2D NMR spectroscopy (1H, 13C, DQF-COSY, TOCSY, GHSQC, GHMQC, ROESY) as well as mass spectrometry (EI and HR-MALDI). (−)-Epicatechin showed weak antiviral activity against Influenza A virus and very weak cytotoxicity against MDCK cells.

Metronidazole prodrugs: synthesis, physicochemical properties, stability, and ex vivo release studies.

The aim of the present study was to develop a colon targeted delivery system for metronidazole using polymeric prodrug formulation. Two chitosan amide conjugates of metronidazole were prepared by using two different spacers to covalently link the drug to the amino group of the chitosan glucosamine units. Glutaric and succinic hemiesters of metronidazole were thus prepared and then coupled to chitosan to obtain metronidazole-glutaryl- and metronidazole-succinyl-chitosan conjugates. Polymeric prodrugs were characterized by solid state NMR method, namely carbon 13 cross polarization magic angle spinning ((13)C NMR CPMAS). Prodrug stability study was carried out in acid (pH = 1.2) and in alkaline (pH = 7.4) buffers in a thermostatic bath at 37 °C. Drug release from the two prodrugs was studied by incubating each of them with 10% w/v cecal and colonic content of rats. Obtained results showed that both prodrugs were adequately stable in acid environment, while the succinyl conjugate was more stable than the glutaryl one in alkaline buffer. Both the prodrugs released the drug in cecal and colonic content, showing that the two systems could serve as colon specific delivery systems of metronidazole.

Metalation reactions: XIII. The reactions of electrophiles with the dilithiated species 1-(α-lithiomethyl)-2-[(α-lithiomethyl)thio]benzene☆

Abstract Direct dimetalation of 1-methyl-2-(methylthio)benzene ( 1 ) gives the dilithiated species ( 2 ) in good yield, which can be used to introduce substituents into the thiomethyl and methyl groups. Species 2 can react also with a variety of dichlorosilanes and dichlorostannanes, and with sulphur chloride, to yield derivatives of 1,3-benzothiasilin, 1,3-benzothiastannin and 1,3-benzodithiin respectively. Reaction of 2 with tetrachlorosilane yields a spirocyclic silicon compound, while reaction with benzoyl chloride yields a derivative of 1-benzothiopyran.

Metallation reactions XXII: Regioselective metallation of (trifluoromethyl)(alkylthio) benzenes

Abstract The metallation reactions of (trifluoromethyl)(alkylthio)benzenes with organolithium reagents and with the butyllithium/potassium tert -butoxide superbasic mixture are here described. The results, according to the theoretical calculations of energy minima, show the monometallation regiochemistry is directed by the sulphur atom. On the other side, the bimetallation, that can be performed only on methylthio derivatives, depends on the organometallic reagent employed. Using butyllithium the stronger coordinative power of sulphur prevails and products metallated in ortho and alpha positions to this atom are mainly formed. With the more basic sec -butyllithium and with the superbase, because of mutual competition between the thioalkyl and trifluoromethyl groups, mixtures of products, coming from metallation in the ortho position to the trifluoromethyl group and in the alpha position of the thiomethylic group, are obtained. In addition, products coming from substitution ortho,alpha to the thiomethyl group are also formed. All mono- and bimetallated intermediates showed to be good synthons for the synthesis of fluoro- and (trifluoromethyl)-substituted benzothiophenes and (trifluoromethyl)benzenes substituted on the thioalkylic chain and/or on the ring.