In the recent years, in the attempt to counteract the detrimental effects of oxidative damages is... more In the recent years, in the attempt to counteract the detrimental effects of oxidative damages is always more convincing the strategy of implementing the diet with antioxidants nutrients, especially deriving from natural sources. Etnobotanical studies have confirmed the high content of antioxidant vitamins in Adansonia digitata fruit constituents and leaves. Baobab fruit pulp can be considered a much valuable source
Several lines of evidence suggest potential benefits by a combination of carotenoids and tocopher... more Several lines of evidence suggest potential benefits by a combination of carotenoids and tocopherols in chronic diseases. Therefore, we have designed FeAOX-6, a novel antioxidant that combines into a single molecule the chroman head of tocopherols and a fragment of lycopene, consisting of a polyisoprenyl sequence of four conjugated double bonds. The ability of FeAOX-6 in inhibiting lipid peroxidation and reactive oxygen species (ROS) production induced by different sources of free radicals (t-BOOH, AAPH, and H2O2) in arachidonic acid solution and in isolated thymocytes was investigated. Its antioxidant efficiency was also compared with that of alpha-tocopherol, lycopene, and a mixture of the two antioxidants. The results strongly suggest that FeAOX-6 can act as a potent antioxidant in our models, by inhibiting malondialdehyde production and ROS generation in a dose- and a time-dependent manner. In the cell model, the compound also provides a higher antioxidant capacity than alpha-to...
A structure-activity relationship (SAR) study on some new 1-β-D-ribofuranosyl-3,4-substituted py... more A structure-activity relationship (SAR) study on some new 1-β-D-ribofuranosyl-3,4-substituted pyrazole derivs. led us to obtain iodo-β-D-ribofuranosylpyrazolecarboxylate I and its 3-methyl-1,2,4-oxadiazole analog at position C3. These compds. showed good potency, wide spectrum of antiproliferative activity and low cytotoxicity against resting peripheral blood lymphocytes (PBL). Although none of the test compds. displayed antiviral activity, I was able to potentiate the anti-HIV-1 activity of dideoxyinosine (ddI), thus behaving like the known inosine monophosphate dehydrogenase (IMPDH) inhibitors ribavirin and tiazofurin. Overall, these results suggest that the target of I may be an enzyme other than IMPDH involved in the purine de novo biopreparation. [on SciFinder(R)]
In a structure activity relationship (SAR) study on azole-related nucleosides we have designed so... more In a structure activity relationship (SAR) study on azole-related nucleosides we have designed some pyrazole-nucleoside analogs, e.g. I (R = H, Me, Bu), characterized for the first time, by a carboxylic ester moiety. 4-Iodo-1-β-D-ribofuranosyl-pyrazole-3-carboxylate showed a wide spectrum of antiproliferative activity and a particularly low cytotoxicity against resting PBL, being, unlike the other azole nucleosides, more active than the corresponding primary amide. [on SciFinder(R)]
The number of methods to measure antioxidants in botanicals, foods, nutraceuticals and other diet... more The number of methods to measure antioxidants in botanicals, foods, nutraceuticals and other dietary supplements are increased considerably in the last 10 years. However most techniques require long experimental times and high costs to determine antioxidant capacity of hydrophilic or lipophilic compound in a food mixture. By means of a photochemiluminescence method, we assessed the Integral Antioxidant Capacity (IAC) which
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Continuing our studies on ribonucleotide reductase (RNR) mechanism-based inhibitors, we have now ... more Continuing our studies on ribonucleotide reductase (RNR) mechanism-based inhibitors, we have now prepared the diphosphates (DP) of 2'-O-allyl-1-beta-D-arabinofuranosyl-uracil and -cytosine and 2'-O-allyl-9-beta-D-arabinofuranosyl-adenine and evaluated their inhibitory activity against recombinant murine RNR. 2'-O-Allyl-araUDP proved to be inhibitory to RNR at an IC(50) of 100 microM, whereas 2'-O-allyl-araCDP was only marginally active (IC(50) 1 mM) and 2'-O-allyl-araADP was completely inactive. The susceptibility of the parent nucleosides to phosphorylation by thymidine kinase and 2'-deoxycytidine kinase was also investigated, and all nucleosides proved to be poor substrates for the above-cited kinases. Moreover, prodrugs of 2'-O-allyl-araU and -araC monophosphates, namely 2'-O-allyl-5'-(phenylethoxy-L-alanyl phosphate)-araU and -araC, were prepared and tested against tumor cell proliferation but proved to be inactive. A molecular modeling study has been conducted in order to explain our results. The data confirm that for both the natural and analogue nucleoside diphosphates, the principal determinant interaction with the active site of RNR is with the diphosphate group, which forms strong hydrogen bonds with Glu623, Thr624, Ser625, and Thr209. Our findings indicate that the poor phosphorylation may represent an explanation for the lack of marked in vitro cytostatic activity of the test compounds.
Recent interest in flavonoids has increased greatly due to their biological and pharmacological a... more Recent interest in flavonoids has increased greatly due to their biological and pharmacological activities. Flavonoids, consist of a large group of low molecular weight polyphenolic substances, naturally occurring in fruits, vegetables, tea, and wine, and are an integral part of the human diet. Rutin is a common dietary flavonoid that is widely consumed worldwide from plant-derived beverages and foods as traditional and folk medicine remedy as well. Rutin exhibit important pharmacological activities, including anti-oxidation, anti-inflammation, anti-diabetic, anti-adipogenic, neuroprotective and hormone therapy. Here, we present the synthesis, antimicrobial, antiproliferative and pro-apoptotic effect on human leukemic K562 cells of compound R2, a new semi-synthetic derivative of Rutin as compared to Rutin itself. The new derivative was also included in finished topical formulations to evaluate a potential application to the dermatology field in view of the antioxidant/antimicrobial/...
Several pyrazole and pyrazolo[4,3-d]-1,2,3-triazin-4-one ribonucleosides were prepared and tested... more Several pyrazole and pyrazolo[4,3-d]-1,2,3-triazin-4-one ribonucleosides were prepared and tested for antiviral/antitumor activities. Appropriate heterocyclic bases were prepared by standard methodologies. Glycosylation of pyrazoles 6a-e,g,i and of pyrazolo[4,3-d]-1,2,3-triazin-4-ones 12f-1 mediated by silylation with hexamethyldisilazane, with 1-beta-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose, gave in good yields the corresponding glycosides 7a-e,g, 8g,i, 13f,h,k, and 14f, but could not be applied to compounds 12g,i,j,l. To overcome this occurrence, a different strategy involving the preparation, diazotization, and in situ cyclization of opportune pyrazole glycosides 9 and 10 was required. Moreover derivatives having the general formula 5 were considered not only as synthetic intermediates in the synthesis of 3 but also as carbon bioisosteres of ribavirin 4. All compounds were evaluated in vitro for cytostatic and antiviral activity. The pyrazolo[4,3-d]-1,2,3-triazin-4-one nucleosides that resulted were substantially devoid of any activity; only 15h,k showed a moderate cytostatic activity against T-cells. However, pyrazole nucleosides 9b,c,e were potent and selective cytotoxic agents against T-lymphocytes, whereas 9e showed a selective, although not very potent, activity against coxsackie B1.
Skin antioxidant network protects cells against oxidative injury and prevents the production of o... more Skin antioxidant network protects cells against oxidative injury and prevents the production of oxidation products. When oxidative stress overwhelms the skin antioxidant capacity, the subsequent modification of the cellular redox apparatus leads to an alteration of cell homeostasis leading to degenerative processes. In the dermocosmetic field, the topical application of antioxidants is often suggested as a possible strategy to prevent and modulate oxidative skin damages. Continuing our studies addressed to set-up new bio-engineering protocols for the claim substantiation of antioxidant cosmetic products, we have developed a new non-invasive methodology for the evaluation of antioxidants cosmetics ingredients and finished products. The effects of a pre-treatment on forearm skin with an antioxidant ingredient were investigated on 15 volunteers, in a double-blind randomised fashion. A non-invasive method was devised that comprises the collection of forehead SC layers of the pre-treated area and control and the next evaluation of skin antioxidant capacity (IAC-S) by a luminescence-based method. The results showed that the antioxidant preparation was able to increase, to a statistically significant extent (P<0.01), the IAC-S in comparison with the control area. The data were confirmed (P<0.05) by comparison with a method, previously developed by us, based on DermAnalyzer. In view of the simplicity and reliability of the method here presented, this new technique is proposed as a possible tool for the routine evaluation of in vivo efficacy of antioxidant functional ingredients and finished products.
The synthesis of model 7 deazapurine derivatives related to tubercidin and toyocamycin has been p... more The synthesis of model 7 deazapurine derivatives related to tubercidin and toyocamycin has been performed. Tubercidin derivatives were obtained by simple conversion of the amino group of the heterocyclic moiety of the starting 7-deazadenosine compounds, into a hydroxyl group. Preparation of toyocamycin derivatives was accomplished by treatment of the silylated 6-bromo-5-cyanopyrrolo[2,3-d]pyrimidin-4-one with 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-d-ribofuranose. The glycosylation reaction afforded a mixture of 8-bromo 7-cyano 2',3',5' tri-O-benzoyl 7-deazainosine and 6-bromo-5-cyano-3-(2',3',5'-tri-O-benzoyl-beta-d-ribofuranosyl)pyrrolo[2,3-d]-pyrimidin-4-one isomers: The structures were assigned on the basis of NMR spectroscopy studies. Next deprotection treatment gave the novel 7-deazainosine ribonucleosides.
Friedreich Ataxia (FRDA), the most frequent inherited ataxia, is not only characterized by progre... more Friedreich Ataxia (FRDA), the most frequent inherited ataxia, is not only characterized by progressive gait and limb ataxia, but in most cases is also accompanied by a severe hypertrophic cardiomyopathy. This life threatening symptom can be ameliorated by the administration of idebenone, a short chain quinone antioxidant, supporting additional evidence that oxidative stress plays a major role in the pathogenesis of this disease. In this study we analyze the combinatorial effect of different antioxidants on cell viability of FRDA fibroblasts and of RAT-1 immortalized fibroblasts exposed to oxidative stress. We find that an equimolar mixture of idebenone and vitamin E is more potent than each of the compound alone. Increased potency was also obtained with a novel synthetic antioxidant (Fe-Aox29) combining the active groups from both idebenone and vitamin E. These results indicate, that idebenone and vitamin E might act synergistically to counteract oxidative stress in fibroblasts from FRDA patients.
Oxidative stress plays a pivotal role in the pathogenesis of several chronic diseases and antioxi... more Oxidative stress plays a pivotal role in the pathogenesis of several chronic diseases and antioxidants may represent potential tools for the prevention of these diseases. Here, we investigated the antioxidant efficiency of different tocotrienol isoforms (alpha-, delta-, gamma-tocotrienols), and that of FeAox-6, a novel synthetic compound which combines, by a stable covalent bond, the chroman head of vitamin E and a polyisoprenyl sequence of four conjugated double bonds into a single molecule. The antioxidant efficiency was evaluated as the ability of the compounds to inhibit lipid peroxidation, reactive oxygen species (ROS) production, heat shock protein (hsp) expression in rat liver microsomal membranes as well as in RAT-1 immortalized fibroblasts challenged with different free radical sources, including 2,2'-azobis(2-amidinopropane) (AAPH), tert-butyl hydroperoxide (tert-BOOH) and H2O2. Our results show that individual tocotrienols display different antioxidant potencies. Irrespective of the prooxidant used, the order of effectiveness was:delta-tocotrienol > gamma-tocotrienol = alpha-tocotrienol in both isolated membranes and intact cells. This is presumably due to the decreased methylation of delta-tocotrienol chromane ring, which allows the molecule to be more easily incorporated into cell membranes. Moreover, we found that FeAox-6 showed an antioxidant potency greater than that of delta-tocotrienol. Such an efficiency seems to depend on the concomitant presence of a chromane ring and a phytyl chain in the molecule, which because of four conjugated double bonds, may induce a greater mobility and a more uniform distribution within cell membrane. In view of these results, FeAox-6 represents a new potential preventive agent in chronic diseases in which oxidative stress plays a pathogenic role.
Chocolate antioxidant properties are often claimed; however, they are frequently different from t... more Chocolate antioxidant properties are often claimed; however, they are frequently different from the parent natural sources due to the industry or artisan transformation. In particular, antioxidant property of chocolate and cocoa are not adequately taken into consideration by consumers who normally make use of this food just for its flavor and taste properties. In this study, we have investigated the antioxidant capacity and total phenolic content of cocoa nibs, cocoa masses, and corresponding chocolate bars with different percentages of cocoa from different origins. The antioxidant capacity of the different samples was measured by two different assays [1,1-diphenyl-2-picryl-hydrazyl radical (DPPH) and ferric reducing antioxidant of potency (FRAP) tests]. The Folin-Ciocalteu reagent was used to assess the total phenolic content. The masses showed a higher antioxidant power than the nibs, and this has been attributed to the fact that in the nibs is still present the lipid part, which will form the cocoa butter. The influence of milk, whey, and soy proteins was also investigated. Our results showed that the extra dark cocoa bar, 100% cocoa chocolate, is the best in terms of total polyphenol content and in terms of antioxidant capacity according to the DPPH and FRAP tests. In addition, the bars of organic dark chocolate 80%, dark Tanzania 80%, and Trinidad 80% products are well performing in all respects. As highlighted by us, the antiradical properties of cocoa products are higher than many antioxidant supplements in tablets.
To improve the entry of certain drugs into brain, ascorbic acid (AA) conjugates of these drugs we... more To improve the entry of certain drugs into brain, ascorbic acid (AA) conjugates of these drugs were synthesized and their capacity to interact with SVCT2 ascorbate transporters was explored. Kinetic studies clearly indicate that all of the conjugates were able to competitively inhibit ascorbate transport in human retinal pigment epithelial cells (HRPE). In vivo studies, in a mouse model system, demonstrate that conjugate 3 is better absorbed compared to the nonconjugated parent drug.
In a dual targeting approach, to explore the ability of tretinoin (all-trans-retinoic acid) to be... more In a dual targeting approach, to explore the ability of tretinoin (all-trans-retinoic acid) to behave as a covalent carrier for cytotoxic entities, conjugates of retinoic acid with a few representative molecules, being important examples of antitumor pharmacophores (i.e., nucleoside analogues and alkylating agents), have been synthesized and tested for their cytostatic and differentiating activity. All compounds were stable to in vitro hydrolysis in human plasma and more lipophilic than the parent compounds, thus consenting enhanced uptake into the cells. Among the nucleoside analogues the Ara-C derivatives 3 and 6 and the Ara-A derivative 7 proved the most cytostatic (IC50 < 0.32 microgram/mL) resulting from 25- to > 144-fold more active (Ara-A derivatives) or at least as equally active (Ara-C derivatives) as compared to the parent nucleosides. Compound 3, endowed with a highly lipophilic silyl moiety at the 3' and 5' positions, showed the highest differentiating activity (54% and 44% differentiated HL-60 cells at 0.2 and 0.05 microgram/mL respectively). With regard to the retinoic acid conjugates of alkylating agents, compound 10 was the most cytostatic agent (IC50 < 0.32 microgram/mL) and the most potent differentiating agent (33-34% at 0.32 and 0.08 microgram/mL). These structures may also be regarded as analogs of either retinoic acid or the cytotoxic compound.
In the recent years, in the attempt to counteract the detrimental effects of oxidative damages is... more In the recent years, in the attempt to counteract the detrimental effects of oxidative damages is always more convincing the strategy of implementing the diet with antioxidants nutrients, especially deriving from natural sources. Etnobotanical studies have confirmed the high content of antioxidant vitamins in Adansonia digitata fruit constituents and leaves. Baobab fruit pulp can be considered a much valuable source
Several lines of evidence suggest potential benefits by a combination of carotenoids and tocopher... more Several lines of evidence suggest potential benefits by a combination of carotenoids and tocopherols in chronic diseases. Therefore, we have designed FeAOX-6, a novel antioxidant that combines into a single molecule the chroman head of tocopherols and a fragment of lycopene, consisting of a polyisoprenyl sequence of four conjugated double bonds. The ability of FeAOX-6 in inhibiting lipid peroxidation and reactive oxygen species (ROS) production induced by different sources of free radicals (t-BOOH, AAPH, and H2O2) in arachidonic acid solution and in isolated thymocytes was investigated. Its antioxidant efficiency was also compared with that of alpha-tocopherol, lycopene, and a mixture of the two antioxidants. The results strongly suggest that FeAOX-6 can act as a potent antioxidant in our models, by inhibiting malondialdehyde production and ROS generation in a dose- and a time-dependent manner. In the cell model, the compound also provides a higher antioxidant capacity than alpha-to...
A structure-activity relationship (SAR) study on some new 1-β-D-ribofuranosyl-3,4-substituted py... more A structure-activity relationship (SAR) study on some new 1-β-D-ribofuranosyl-3,4-substituted pyrazole derivs. led us to obtain iodo-β-D-ribofuranosylpyrazolecarboxylate I and its 3-methyl-1,2,4-oxadiazole analog at position C3. These compds. showed good potency, wide spectrum of antiproliferative activity and low cytotoxicity against resting peripheral blood lymphocytes (PBL). Although none of the test compds. displayed antiviral activity, I was able to potentiate the anti-HIV-1 activity of dideoxyinosine (ddI), thus behaving like the known inosine monophosphate dehydrogenase (IMPDH) inhibitors ribavirin and tiazofurin. Overall, these results suggest that the target of I may be an enzyme other than IMPDH involved in the purine de novo biopreparation. [on SciFinder(R)]
In a structure activity relationship (SAR) study on azole-related nucleosides we have designed so... more In a structure activity relationship (SAR) study on azole-related nucleosides we have designed some pyrazole-nucleoside analogs, e.g. I (R = H, Me, Bu), characterized for the first time, by a carboxylic ester moiety. 4-Iodo-1-β-D-ribofuranosyl-pyrazole-3-carboxylate showed a wide spectrum of antiproliferative activity and a particularly low cytotoxicity against resting PBL, being, unlike the other azole nucleosides, more active than the corresponding primary amide. [on SciFinder(R)]
The number of methods to measure antioxidants in botanicals, foods, nutraceuticals and other diet... more The number of methods to measure antioxidants in botanicals, foods, nutraceuticals and other dietary supplements are increased considerably in the last 10 years. However most techniques require long experimental times and high costs to determine antioxidant capacity of hydrophilic or lipophilic compound in a food mixture. By means of a photochemiluminescence method, we assessed the Integral Antioxidant Capacity (IAC) which
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Continuing our studies on ribonucleotide reductase (RNR) mechanism-based inhibitors, we have now ... more Continuing our studies on ribonucleotide reductase (RNR) mechanism-based inhibitors, we have now prepared the diphosphates (DP) of 2'-O-allyl-1-beta-D-arabinofuranosyl-uracil and -cytosine and 2'-O-allyl-9-beta-D-arabinofuranosyl-adenine and evaluated their inhibitory activity against recombinant murine RNR. 2'-O-Allyl-araUDP proved to be inhibitory to RNR at an IC(50) of 100 microM, whereas 2'-O-allyl-araCDP was only marginally active (IC(50) 1 mM) and 2'-O-allyl-araADP was completely inactive. The susceptibility of the parent nucleosides to phosphorylation by thymidine kinase and 2'-deoxycytidine kinase was also investigated, and all nucleosides proved to be poor substrates for the above-cited kinases. Moreover, prodrugs of 2'-O-allyl-araU and -araC monophosphates, namely 2'-O-allyl-5'-(phenylethoxy-L-alanyl phosphate)-araU and -araC, were prepared and tested against tumor cell proliferation but proved to be inactive. A molecular modeling study has been conducted in order to explain our results. The data confirm that for both the natural and analogue nucleoside diphosphates, the principal determinant interaction with the active site of RNR is with the diphosphate group, which forms strong hydrogen bonds with Glu623, Thr624, Ser625, and Thr209. Our findings indicate that the poor phosphorylation may represent an explanation for the lack of marked in vitro cytostatic activity of the test compounds.
Recent interest in flavonoids has increased greatly due to their biological and pharmacological a... more Recent interest in flavonoids has increased greatly due to their biological and pharmacological activities. Flavonoids, consist of a large group of low molecular weight polyphenolic substances, naturally occurring in fruits, vegetables, tea, and wine, and are an integral part of the human diet. Rutin is a common dietary flavonoid that is widely consumed worldwide from plant-derived beverages and foods as traditional and folk medicine remedy as well. Rutin exhibit important pharmacological activities, including anti-oxidation, anti-inflammation, anti-diabetic, anti-adipogenic, neuroprotective and hormone therapy. Here, we present the synthesis, antimicrobial, antiproliferative and pro-apoptotic effect on human leukemic K562 cells of compound R2, a new semi-synthetic derivative of Rutin as compared to Rutin itself. The new derivative was also included in finished topical formulations to evaluate a potential application to the dermatology field in view of the antioxidant/antimicrobial/...
Several pyrazole and pyrazolo[4,3-d]-1,2,3-triazin-4-one ribonucleosides were prepared and tested... more Several pyrazole and pyrazolo[4,3-d]-1,2,3-triazin-4-one ribonucleosides were prepared and tested for antiviral/antitumor activities. Appropriate heterocyclic bases were prepared by standard methodologies. Glycosylation of pyrazoles 6a-e,g,i and of pyrazolo[4,3-d]-1,2,3-triazin-4-ones 12f-1 mediated by silylation with hexamethyldisilazane, with 1-beta-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose, gave in good yields the corresponding glycosides 7a-e,g, 8g,i, 13f,h,k, and 14f, but could not be applied to compounds 12g,i,j,l. To overcome this occurrence, a different strategy involving the preparation, diazotization, and in situ cyclization of opportune pyrazole glycosides 9 and 10 was required. Moreover derivatives having the general formula 5 were considered not only as synthetic intermediates in the synthesis of 3 but also as carbon bioisosteres of ribavirin 4. All compounds were evaluated in vitro for cytostatic and antiviral activity. The pyrazolo[4,3-d]-1,2,3-triazin-4-one nucleosides that resulted were substantially devoid of any activity; only 15h,k showed a moderate cytostatic activity against T-cells. However, pyrazole nucleosides 9b,c,e were potent and selective cytotoxic agents against T-lymphocytes, whereas 9e showed a selective, although not very potent, activity against coxsackie B1.
Skin antioxidant network protects cells against oxidative injury and prevents the production of o... more Skin antioxidant network protects cells against oxidative injury and prevents the production of oxidation products. When oxidative stress overwhelms the skin antioxidant capacity, the subsequent modification of the cellular redox apparatus leads to an alteration of cell homeostasis leading to degenerative processes. In the dermocosmetic field, the topical application of antioxidants is often suggested as a possible strategy to prevent and modulate oxidative skin damages. Continuing our studies addressed to set-up new bio-engineering protocols for the claim substantiation of antioxidant cosmetic products, we have developed a new non-invasive methodology for the evaluation of antioxidants cosmetics ingredients and finished products. The effects of a pre-treatment on forearm skin with an antioxidant ingredient were investigated on 15 volunteers, in a double-blind randomised fashion. A non-invasive method was devised that comprises the collection of forehead SC layers of the pre-treated area and control and the next evaluation of skin antioxidant capacity (IAC-S) by a luminescence-based method. The results showed that the antioxidant preparation was able to increase, to a statistically significant extent (P<0.01), the IAC-S in comparison with the control area. The data were confirmed (P<0.05) by comparison with a method, previously developed by us, based on DermAnalyzer. In view of the simplicity and reliability of the method here presented, this new technique is proposed as a possible tool for the routine evaluation of in vivo efficacy of antioxidant functional ingredients and finished products.
The synthesis of model 7 deazapurine derivatives related to tubercidin and toyocamycin has been p... more The synthesis of model 7 deazapurine derivatives related to tubercidin and toyocamycin has been performed. Tubercidin derivatives were obtained by simple conversion of the amino group of the heterocyclic moiety of the starting 7-deazadenosine compounds, into a hydroxyl group. Preparation of toyocamycin derivatives was accomplished by treatment of the silylated 6-bromo-5-cyanopyrrolo[2,3-d]pyrimidin-4-one with 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-d-ribofuranose. The glycosylation reaction afforded a mixture of 8-bromo 7-cyano 2',3',5' tri-O-benzoyl 7-deazainosine and 6-bromo-5-cyano-3-(2',3',5'-tri-O-benzoyl-beta-d-ribofuranosyl)pyrrolo[2,3-d]-pyrimidin-4-one isomers: The structures were assigned on the basis of NMR spectroscopy studies. Next deprotection treatment gave the novel 7-deazainosine ribonucleosides.
Friedreich Ataxia (FRDA), the most frequent inherited ataxia, is not only characterized by progre... more Friedreich Ataxia (FRDA), the most frequent inherited ataxia, is not only characterized by progressive gait and limb ataxia, but in most cases is also accompanied by a severe hypertrophic cardiomyopathy. This life threatening symptom can be ameliorated by the administration of idebenone, a short chain quinone antioxidant, supporting additional evidence that oxidative stress plays a major role in the pathogenesis of this disease. In this study we analyze the combinatorial effect of different antioxidants on cell viability of FRDA fibroblasts and of RAT-1 immortalized fibroblasts exposed to oxidative stress. We find that an equimolar mixture of idebenone and vitamin E is more potent than each of the compound alone. Increased potency was also obtained with a novel synthetic antioxidant (Fe-Aox29) combining the active groups from both idebenone and vitamin E. These results indicate, that idebenone and vitamin E might act synergistically to counteract oxidative stress in fibroblasts from FRDA patients.
Oxidative stress plays a pivotal role in the pathogenesis of several chronic diseases and antioxi... more Oxidative stress plays a pivotal role in the pathogenesis of several chronic diseases and antioxidants may represent potential tools for the prevention of these diseases. Here, we investigated the antioxidant efficiency of different tocotrienol isoforms (alpha-, delta-, gamma-tocotrienols), and that of FeAox-6, a novel synthetic compound which combines, by a stable covalent bond, the chroman head of vitamin E and a polyisoprenyl sequence of four conjugated double bonds into a single molecule. The antioxidant efficiency was evaluated as the ability of the compounds to inhibit lipid peroxidation, reactive oxygen species (ROS) production, heat shock protein (hsp) expression in rat liver microsomal membranes as well as in RAT-1 immortalized fibroblasts challenged with different free radical sources, including 2,2'-azobis(2-amidinopropane) (AAPH), tert-butyl hydroperoxide (tert-BOOH) and H2O2. Our results show that individual tocotrienols display different antioxidant potencies. Irrespective of the prooxidant used, the order of effectiveness was:delta-tocotrienol > gamma-tocotrienol = alpha-tocotrienol in both isolated membranes and intact cells. This is presumably due to the decreased methylation of delta-tocotrienol chromane ring, which allows the molecule to be more easily incorporated into cell membranes. Moreover, we found that FeAox-6 showed an antioxidant potency greater than that of delta-tocotrienol. Such an efficiency seems to depend on the concomitant presence of a chromane ring and a phytyl chain in the molecule, which because of four conjugated double bonds, may induce a greater mobility and a more uniform distribution within cell membrane. In view of these results, FeAox-6 represents a new potential preventive agent in chronic diseases in which oxidative stress plays a pathogenic role.
Chocolate antioxidant properties are often claimed; however, they are frequently different from t... more Chocolate antioxidant properties are often claimed; however, they are frequently different from the parent natural sources due to the industry or artisan transformation. In particular, antioxidant property of chocolate and cocoa are not adequately taken into consideration by consumers who normally make use of this food just for its flavor and taste properties. In this study, we have investigated the antioxidant capacity and total phenolic content of cocoa nibs, cocoa masses, and corresponding chocolate bars with different percentages of cocoa from different origins. The antioxidant capacity of the different samples was measured by two different assays [1,1-diphenyl-2-picryl-hydrazyl radical (DPPH) and ferric reducing antioxidant of potency (FRAP) tests]. The Folin-Ciocalteu reagent was used to assess the total phenolic content. The masses showed a higher antioxidant power than the nibs, and this has been attributed to the fact that in the nibs is still present the lipid part, which will form the cocoa butter. The influence of milk, whey, and soy proteins was also investigated. Our results showed that the extra dark cocoa bar, 100% cocoa chocolate, is the best in terms of total polyphenol content and in terms of antioxidant capacity according to the DPPH and FRAP tests. In addition, the bars of organic dark chocolate 80%, dark Tanzania 80%, and Trinidad 80% products are well performing in all respects. As highlighted by us, the antiradical properties of cocoa products are higher than many antioxidant supplements in tablets.
To improve the entry of certain drugs into brain, ascorbic acid (AA) conjugates of these drugs we... more To improve the entry of certain drugs into brain, ascorbic acid (AA) conjugates of these drugs were synthesized and their capacity to interact with SVCT2 ascorbate transporters was explored. Kinetic studies clearly indicate that all of the conjugates were able to competitively inhibit ascorbate transport in human retinal pigment epithelial cells (HRPE). In vivo studies, in a mouse model system, demonstrate that conjugate 3 is better absorbed compared to the nonconjugated parent drug.
In a dual targeting approach, to explore the ability of tretinoin (all-trans-retinoic acid) to be... more In a dual targeting approach, to explore the ability of tretinoin (all-trans-retinoic acid) to behave as a covalent carrier for cytotoxic entities, conjugates of retinoic acid with a few representative molecules, being important examples of antitumor pharmacophores (i.e., nucleoside analogues and alkylating agents), have been synthesized and tested for their cytostatic and differentiating activity. All compounds were stable to in vitro hydrolysis in human plasma and more lipophilic than the parent compounds, thus consenting enhanced uptake into the cells. Among the nucleoside analogues the Ara-C derivatives 3 and 6 and the Ara-A derivative 7 proved the most cytostatic (IC50 < 0.32 microgram/mL) resulting from 25- to > 144-fold more active (Ara-A derivatives) or at least as equally active (Ara-C derivatives) as compared to the parent nucleosides. Compound 3, endowed with a highly lipophilic silyl moiety at the 3' and 5' positions, showed the highest differentiating activity (54% and 44% differentiated HL-60 cells at 0.2 and 0.05 microgram/mL respectively). With regard to the retinoic acid conjugates of alkylating agents, compound 10 was the most cytostatic agent (IC50 < 0.32 microgram/mL) and the most potent differentiating agent (33-34% at 0.32 and 0.08 microgram/mL). These structures may also be regarded as analogs of either retinoic acid or the cytotoxic compound.
Uploads
Papers by Silvia Vertuani