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The γ-butyrolactone and δ-valerolactone structural units are present in different natural products with significant pharmacological properties. Fumaric acid ester-based drugs are used for the treatment of psoriasis and, more recently, multiple sclerosis. We synthesized different γ-butyrolactone and δ-valerolactone derivatives where the fumarate moiety is forced into a lactone ring in search of strategies to maintain the anti-inflammatory activity of fumaric acid esters limiting the side effects and enhancing the bioavailability. The structures of all synthesized compounds obtained were identified on the basis of their spectral data. The toxicity profile as well as the neuroprotective properties of the synthesized derivatives were evaluated in human neuroblastoma SH-SY5Y cell line. All tested fumaric esters presented lower cytotoxicity and higher neuroprotective properties, in comparison to dimethyl fumarate. Pre-treatment of cells with at least seven compounds for 24 h lead to a significantly neuroprotection against H2O2-induced cell damage. Our results demonstrate that SH-SY5Y cells are suitable cellular model to evaluate the neuroprotective role of fumaric acid esters, and support further evaluation of BG-12 derivatives aimed at decreasing cytotoxicity and limiting the side effects for improvement of treatments for multiple sclerosis and psoriasis.

CoQ10 and Vitamin E are used in medicinal applications, but they are both lipophilic molecules and the poor solubility in aqueous media results in an inefficient administration, poor bioavailability and potential toxicity. A mixed conjugate Ubiquinol-Polyethylene glycol-Vitamin E was synthesized and characterized to improve the bioavailability of CoQ10 and Vitamin E. The synthesized mixed PEG conjugate was characterized by 1H NMR spectroscopy and MALDI spectrometry. The in vitro release of the conjugate was measured at various pH conditions and in human plasma and the evaluation of free CoQ10 and Vitamin E were also conducted. The obtained results demonstrated that more CoQ10 and Vitamin E were released from PEG conjugate at pH 7.4 and in plasma within the 24 h. The antioxidant activity evaluation was carried out by DPPH assay. Our results indicated that the chemical modification after esterification with PEG of the two drugs Ubiquinol and Vitamin E doesn't significantly affected their antioxidant potential.

In the attempt of prolonging the effect of drugs, a new branched, high-molecular weight multimeric poly(ethylene glycol) (MultiPEG), synthesized with a simple assembling procedure that devised the introduction of functional groups with divergent and selective reactivity, was employed as drug carrier. In particular, the attention was focused on the study of theophylline (THEO) and THEO-MultiPEG conjugates pharmacokinetic after oral administration in rabbit. Pharmacokinetic behaviour was studied according to an ad hoc developed mathematical model accounting for THEO-MultiPEG in vivo absorption and decomposition into drug (THEO) and carrier (MultiPEG). The branched high-molecular weight MultiPEG proved to be a reliable drug delivery system able to prolong theophylline staying in the blood after oral administration of a THEO-MultiPEG solution. The analysis of experimental data by means of the developed mathematical model revealed that the prolongation of THEO effect was essentially due to the low THEO-MultiPEG permeability in comparison to that of pure THEO

Monoglucosyl and monogalactosyl diglycerides (MGDGs) with medium-long length acyl chains, identified as active components in Euphorbiaceae, were synthesized. They were examined for antimicrobial activity against Gram-positive, Gram-negative bacteria and fungi. MGDGs with two octanoyl groups at both 1- and 2-positions showed the most potent activity. The stereoselectivity of pancreatic lipase was investigated in vitro where the preference for the 1 position in MGDGs is strictly related to the length of the acyl chains.

The regioselective total synthesis of the natural cerebroside (2R,15Z)-N-{(1S,2S,3R,4R,5Z)-1-[(β-D-glucopyranosyloxy)methyl]-2,3,4-trihydroxyheptadec-5-en-1-yl}-2-hydroxytetracos-15-enamide (2), originally isolated from Euphorbiaceae, is reported in full detail.

Monogalactosyl diglycerides with medium to long fatty acid acyl chains, were prepared and examined for antimicrobial activity against Gram positive, Gram negative bacteria and fungi. The study of their in vitro antimicrobial activity confirms the significant activity of some monogalactosyl diacylglycerol analogues and establishes for the galactose series that the 1,2-disubstitution and the octanoyl chain are the proper structural features for the maximum activity.

Two new triterpene acids (1, 2), together with a complex mixture of lecithins (3), were isolated from the fungus Gloeophyllum odoratum. Their structures were elucidated on the basis of extensive spectroscopic analyses. The extract of Gloeophyllum odoratum considerably inhibited thrombin (72% at a concentration of 120 μg/mL); the less polar fraction of the methanolic extract from the mushroom exhibited interesting activity (47% at a concentration of 120 μg/mL) against thrombin. Compounds 1 and 2 were responsible for this activity.

The methanolic extract of the plant Euphorbia helioscopia L. exhibited an interesting free-radical scavenging activity. From the aerial parts of Euphorbia helioscopia L. (Euphorbiaceae), a complex mixture of seven cerebrosides together with glucoclionasterol, a digalactosyldiacylglycerol and a diacylmonogalactosylglycerol were identified. The structures of the cerebrosides were characterized as 1-O-β- d -glucosides of phytosphingosines, which comprised (2S, 3S, 4E, 8E)-2-amino-4(E),8(E)-octadecadiene-1,3-diol, (2S, 3S, 4E, 8Z)-2-amino-4(E),8(Z)-octadecadiene-1,3-diol, (2S, 3S, 4R, 8Z)-2-amino-8(Z)-octadecene-1,3,4-triol as long chain bases with seven 2-hydroxy fatty acids of varying chain lengths (C16, C24:1, C26:1, C24, C26, C28:1) linked to the amino group. The glycosylglycerides were characterized as (2S)-2,3-O-di-(9,12,15-octadecatrienoyl)-glyceryl-6-O-(α- d -galactopyranosyl)-β- d -galactopyranoside and (2S)-2,3-O-di-(9,12,15-octadecatrienoyl)-glyceryl-1-O-β- d -galactopyranoside. The structures were established on the basis of spectroscopic data and chemical reactions.

A new series of triazolotriazines variously substituted at the C5 and N7 (5-25) positions was synthesized and fully characterized at the four adenosine receptor (AR) subtypes. In particular, arylacetyl or arylcarbamoyl moieties were introduced at the N7 position, which enhanced affinity at the hA(2B) and hA(3) ARs, respectively, when utilized on the pyrazolo-triazolopyrimidine nucleus as we reported in the past. In general, compounds with a free amino group at the 7 position (5, 6), showed good affinity at the rat (r) A(2A) AR (range 18.3-96.5nM), while the introduction of a phenylcarbamoyl moiety at the N7 position (12, 19, 24) slightly increased the affinity at the hA(3) AR (range 311-633nM) with respect to the unsubstituted derivatives. The binding profiles of the synthesized analogues seemed to correlate with the substitutions at the C5 and N7 positions. At the hA(2B) AR, derivative 5, which contained a free amino group at the 7 position, was the most potent (EC(50) 3.42microM) and could represent a starting point for searching new non-xanthine hA(2B) AR antagonists. Molecular models of the rA(2A) and hA(3) ARs were constructed by homology to the recently reported crystallographic structure of the hA(2A) AR. A preliminary receptor-driven structure-activity relationship (SAR) based on the analysis of antagonist docking has been provided.

The gating of the CFTR chloride channel is altered by a group of mutations that cause cystic fibrosis. This gating defect may be corrected by small molecules called potentiators. Some 1,4-dihydropyridine (DHP) derivatives, bearing a thiophen-2-yl and a furanyl ring at the 4-position of the nucleus, were prepared and tested as CFTR potentiators. In particular, we evaluated the ability of novel DHPs to enhance the activity of the rescued DeltaF508-CFTR as measured with a functional assay based on the halide-sensitive yellow fluorescent protein. Most DHPs showed an effect comparable to or better than that of the reference compound genistein. The potency was instead significantly improved, with some compounds, such as 3g, 3h, 3n, 4a, 4b, and 4d, having a half effective concentration in the submicromolar range. CoMFA analysis gave helpful suggestions to improve the activity of DHPs.

A new and efficient method for the synthesis of PEG-6-mercaptopurine is described. The key feature of the proposed approach is the protection of the thiol group against metabolic inactivation. Preliminary in vivo and in vitro evaluations of the macromolecular prodrug have been carried out.

The successful conjugation of active theophylline molecules to two new multifunctional high-molecular weight poly(ethylene glycol) derivatives (MultiPEG) and their pharmacokinetic evaluations are reported. The drug loading was increased up to six times in comparison with commercial PEG of the same molecular weight. A clear increase of the time of persistence within the body and a concomitant improvement of the overall pharmacokinetic properties of those prodrugs were also observed. These studies sustain the use of these new PEG-based polymeric supports as a valuable alternative for an effective drug delivery system.

From the fungus Stereum hirsutum have been isolated and identified two new epidioxysterols 1, 4, together with two known ones 2 and 3. Their structures were elucidated on the basis of spectroscopic analysis and chemical reactions. Epidioxysterols 1-4 have been shown to possess a significant activity against Mycobacterium tuberculosis.

Monogalactosyl diglycerides with medium to long fatty acid acyl chains, were prepared and examined for antimicrobial activity against Gram positive, Gram negative bacteria and fungi. The study of their in vitro antimicrobial activity confirms the significant activity of some monogalactosyl diacylglycerol analogues and establishes for the galactose series that the 1,2-disubstitution and the octanoyl chain are the proper structural features for the maximum activity.

The synthesis of a series of α-methylene-γ-butyrolactones (compounds 4a, 4b, 6–12, 16, 17) and α,β-unsaturated-δ-lactones (compounds 19−23, 25, 26) starting from 4,4-dimethyldihydrofuran-2,3-dione (1) has been described. Their chemical structures were assigned by spectroscopic evidence. These new compounds exhibited significantly different antiproliferative properties against cultured human tumor cell lines with their IC50 values ranging from 0.88 to > 20.00 μM.

In the present paper two theophylline esters with poly (ethylene glycol) (PEG) and methoxy poly (ethylene glycol) (mPEG) were prepared. Quantitative yields of the pure products were obtained. Unlike the free drug, the drug-polymer conjugates are freely water-soluble at room temperature. In vitro release experiments in aqueous buffer demonstrate that both conjugates are stable in buffer of pH 7.4 and 1.2. In vivo release studies after oral administration of theophylline conjugates demonstrate a good release of parent drug.

The two enantiomers of acetyl cycloserine 8 , the immediate precursors of the chiral forms of cycloserine 1 , were prepared in enantiomeric excess higher than 98% by means of lipase-catalyzed hydrolysis of 3-benzyloxy-4-hydroxy-Δ 2 -isoxazoline butyrate (±)- 5 . Among the five lipases tested, lipase from Chromobacterium viscosum was by far the most selective catalyst. Since the enantiomeric ratio (E) of the reaction was higher than 100, the hydrolysis spontaneously stopped at 50% conversion to yield (R)-3-benzyloxy-4-hydroxy-Δ 2 -isoxazoline [(R)-(+)- 4 ] and (S)-3-benzyloxy-4-hydroxy-Δ 2 -isoxazoline butyrate [(S)-(−)-5] in almost enantiomerically pure form. Intermediates (R)-(+)- 4 and (S)-(−)- 5 were transformed into the enantiomers of acetyl cycloserine through a four step sequence. This strategy constitutes a valid alternative to the previously reported procedures.