704 research outputs found
Silibinin phosphate-based flavonolignans: new emerging synthetic metabolites with interesting pharmacological properties
No full textMany drug candidates have been reported to possess a strong therapeutic potential in vitro but they have failed in vivo because of their poor pharmacokinetic behaviour, very often due to the low water solubility. There are many formulations and drug design strategies that can be used to overcome solubility issues. The design and synthesis of soluble pro-drugs is one of the most common approach used. In this frame, the phosphate group is a useful tool for the enhancement of aqueous solubility of phenolic and other metabolites, in addition it displayed excellent chemical stability and rapid bioconversion in vivo to the parent drug by phosphatases. On the other hand, also the conjugation of specific molecules recognized by a receptor on the target cell could be a successful strategy. In our studies, we have combined both aspects through the synthesis of new phosphodiester modified Silibinin with a good water solubility, as well as, attractive antioxidant properties. In the past
decade, Silibinin has received more attention due to its large variety of activities ranging from anticancer and chemopreventive actions to hypocholesterolemic, cardioprotective and neuroprotective activities. Unfortunately, the bioavailability and the therapeutic efficiency of Silibinin are rather limited by its low water-solubility. In this work, we present the synthesis of a new library of modified Silibinins and related studies of their redox behaviour. Exploiting the selective protection of the hydroxyl groups of the Silibinin, we developed an efficient strategy for the synthesis of Silibinin phosphate-based flavonolignans consisting of phosphodiester
glycoconjugates and dimers of Silibinin. The water solubility, the radical scavenger efficiency and the ability to scavenge different reactive oxygen species (ROS) have been evaluated for the new phosphodiester modified Silibinins in comparison to Silibinin. Moreover, the serum stability, and their cytoprotective (X/XO assay on HepG2 cells) behaviours have been studied. The remarkable antioxidant activity and the high water solubility (compared to Silibinin) make Silibinin phosphatebased
flavonolignans promising molecules for future studies
Silibinin phosphate-based flavonolignans: new emerging synthetic metabolites with interesting pharmacological properties
No full textMany drug candidates have been reported to possess a strong therapeutic potential in vitro but they have failed in vivo because of their poor pharmacokinetic behaviour, very often due to the low water solubility. There are many formulations and drug design strategies that can be used to overcome solubility issues. The design and synthesis of soluble pro-drugs is one of the most common approach used. In this frame, the phosphate group is a useful tool for the enhancement of aqueous solubility of phenolic and other metabolites, in addition it displayed excellent chemical stability and rapid bioconversion in vivo to the parent drug by phosphatases. On the other hand, also the conjugation of specific molecules recognized by a receptor on the target cell could be a successful strategy. In our studies, we have combined both aspects through the synthesis of new phosphodiester modified Silibinin with a good water solubility, as well as, attractive antioxidant properties. In the past
decade, Silibinin has received more attention due to its large variety of activities ranging from anticancer and chemopreventive actions to hypocholesterolemic, cardioprotective and neuroprotective activities. Unfortunately, the bioavailability and the therapeutic efficiency of Silibinin are rather limited by its low water-solubility. In this work, we present the synthesis of a new library of modified Silibinins and related studies of their redox behaviour. Exploiting the selective protection of the hydroxyl groups of the Silibinin, we developed an efficient strategy for the synthesis of Silibinin phosphate-based flavonolignans consisting of phosphodiester
glycoconjugates and dimers of Silibinin. The water solubility, the radical scavenger efficiency and the ability to scavenge different reactive oxygen species (ROS) have been evaluated for the new phosphodiester modified Silibinins in comparison to Silibinin. Moreover, the serum stability, and their cytoprotective (X/XO assay on HepG2 cells) behaviours have been studied. The remarkable antioxidant activity and the high water solubility (compared to Silibinin) make Silibinin phosphatebased
flavonolignans promising molecules for future studies
Polidocanol foam sclerotherapy in hemorrhoidal disease: shifting the focus to symptom relief, safety and repeatability
No full textHistory of gymnemic acid, a molecule that does not exist
No full textIn the literature there are hundreds of articles, the first dating back to 1866 and the last to 2014, on gymnemic acid, isolated from Gymnema sylvestre, from its
isolation to the determination of its biological activities. Gymnemic acid has a CAS number but its structure is not specified. Studies during the second half of
the 1970s clearly demonstrated that what was being referred to as gymnemic acid is actually a very complex mixture of dozens of substances, belonging to
different classes of natural compounds. This plant, whose infusions or complex mixtures of its metabolites are the basis for many formulas sold in pharmacies
and by herbalists, has anti-diabetic and slimming effects. It is certainly misleading to talk about gymnemic acid as a specific molecule. There may be doubts
about the exact composition of the products, and consequently about their origin and the claimed effect
New silibinin glyco-conjugates: Synthesis and evaluation of antioxidant properties
No full textNew silibinin glyco-conjugates have been synthesized by efficient method and in short time. Exploiting our solution phase strategy, several structurally diverse silibinin glyco-conjugates (gluco, manno, galacto, and lacto-) were successfully realized in very good yields and in short time. In preliminary study to evaluate their antioxidant and neuroprotective activities new derivatives were subjected to DPPH free radical scavenging assay and the Xanthine oxidase (XO) inhibition models assay. Irrespective of the sugar moiety examined, new glyco-conjugates are more than 50 times water-soluble of silibinin. In the other hand they exhibit a radical scavenging activities slightly higher than to silibinin and XO inhibition at least as silibinin. (C) 2014 Elsevier Ltd. All rights reserved
Synthesis and characterization of new modified metabolites, molecules with strong pharmacological activities
No full textPolyphenols are the most widely distributed class of plant secondary metabolites and several thousand different compounds have been identified. They play many different roles in plant biology and human life, as UV protective agents, defensive compounds against herbivores and pathogens, they contribute to plant colors and to the taste of food and drink. Moreover it is widely known that natural metabolites have played a crucial role in the identification of many of the drugs that are on the market today. Nowadays natural products used pure in pharmacological preparations represent only 5% of the total, but their semi-synthesis derivatives represent more than 50% of the drugs in use.(1)
My PhD project is focused on the chemistry of natural substances, and I developed some strategies to synthetize new silibinin conjugates. Silibinin is the major biologically active component of the seeds extract of the milk thistle (Silybum marianum) also known as silymarin.(2) Structurally, silibinin is a diastereoisomeric mixture of two flavonolignans, silybin A and silybin B in a ratio of approximately 1:1.(3)
Silibinin is a metabolite with multiple biological activities operating at various cell levels.(4) Unfortunately, its therapeutic efficiency is rather limited by its low bioavailability due to its very low water solubility.
Aiming to improve the solubility, during the first year of my PhD project, we have developed an efficient synthetic procedure to obtain new 9”-phosphodiester silibinin conjugates with different mono- and di-saccharide labels through the anomeric hydroxyl group.(5)
In our approach 9’’-phosphoramidite has been used as silibinin substrate and 1-OH full protected mono- and disaccharide derivatives as sugar starting materials. We initially converted full acetylated mono and di-saccharides into 1-OH derivatives and these compounds were coupled with 9’’-phosphoramidite silibinin. The oxidation and the deprotection treatments led to the desired phosphodiester derivatives in good yields. The crude materials were then subjected to the purification by reverse phase analysis (RP-18 HPLC), using a variety of columns and elution conditions, but unfortunately it was too difficult to purify the mixture of diastereoisomers. In the end new silibinin analogues were obtained as a mixture of diastereoisomers, observed by 31P NMR analysis. The NMR analysis has proved to be very complex, in fact 1H and 31P NMR spectra of all compounds showed a dramatic complexity, due to the presence of a lot of diastereoisomers. This drawback has not allowed a complete and detailed NMR characterization of the new derivatives. The structures were confirmed by 31P NMR and ESI-MS mass spectra signals. In preliminary study, new derivatives were subjected to DPPH free radical scavenging and Xanthine Oxidase inhibition assays to evaluate their antioxidant activities. Independently of the sugar moiety present, all compounds exhibited a radical scavenging activities slightly higher than that of the silibinin, and Xanthine Oxidase inhibition at least as that of the silibinin. On the other hand the new derivatives showed a water solubility well above that of silibinin, in fact it was possible to prepare solutions of about 70 mg/mL in water.
These two data encouraged our studies during my second year of PhD to improve this synthetic strategy and to realize libraries of optically pure glyco-conjugated silibinins.
The 9''-phosphoramidite has been used as silibinin substrate and fully protected 6-OH mono- and di-saccharide derivatives as sugar starting materials.(6)
We initially converted opportunely protected mono- and di-saccharides (Glucose, Mannose, Galactose, N- Acetylglucosamine, Trehalose and Lactose) into 6-OH derivatives and then they were coupled with 9"-phosphoramidite silibinin following typical phosphoramidite chemistry procedure. The crude materials were purified by reverse phase chromatography (RP-18 HPLC) and characterized by NMR and MALDI- TOF/TOF-MS analyses. All compounds were obtained in good yields and as a mixture of two silibinin diastereoisomers (A and B). Finally new phosphodiester derivatives were converted into the corresponding sodium salt by cation exchange resin carrying crystalline samples. New derivatives showed water solubility well above that of silibinin, with the possibility to prepare solutions of about 70 mg/mL in water. The stability of new glyco-conjugates was investigated in human serum by HPLC analyses and the 50% disappearance of the peak corresponding to the intact glyco-conjugate was observed after ca. 40-68 hours. All derivatives were subjected to DPPH free radical scavenging assay and they exhibited radical scavenging activities slightly higher than that of the silibinin. In order to verify the potential biological properties of these derivatives, a biological assay was used to evaluate the cytotoxicity of the new glyco-conjugates, compared with that of the silibinin, on human liver cancer cell line (Hep G2). No significant changes in the viability of treated cells were observed when they were subjected to the action of glyco-conjugates, also considering the longest incubation (72 hours) at the maximum dose taken (30 µM). Also, in order to investigate the role of the different OH groups in the antioxidant activity of new glyco-conjugates in comparison with silibinin, their acidity and redox capacity have been evaluated. A redox-deep characterization was carried out in collaboration with Prof. Mauro Iuliano and Dr Gaetano De Tommaso of our Department, using potentiometric and voltammetric techniques. The determination of the acidity constants was conducted by potentiometric titrations measuring the concentration of hydrogen ions with a glass electrode. By processing data, it was possible to define three equilibrium constants. Analysis of the data shows that the conjugation in position 9" does not affect the redox behaviour of the silibinin scaffold.
As a part of our continuing research effort towards the synthesis of new natural product analogues exploiting the phosphoramidite chemistry, in the last year of my PhD project the attention was focused on the development of synthetic methods to obtain oligoflavonoids based on silibinin, and to investigate their anti-radical activity. Exploiting the selective protection to hydroxyl groups of the silibinin we have developed an efficient strategy for the synthesis of new 3-9", 3-3 and 9"-9" dimers of silibinin in good yields.(7)
In order to obtain suitable building blocks for the dimers synthesis, we have developed a selective protective reaction for the different hydroxyl groups with isobutyric anhydride. The building blocks obtained were coupled in the three different provisions with 3- and 9”-silibinin phosphoramidite using the well known phosphoramidite chemistry. After oxidation, deprotection and RP-18 HPLC purification the products were converted into the corresponding sodium salts by cation exchange on a DOWEX (Na+ form) resin, leading to the desired phosphodiester dimers derivatives in good yields. The structures of new analogues were confirmed by 31P NMR and MALDI-TOF/TOF-MS analyses. The stability of new silibinin dimers was investigated in human serum by HPLC analysis and the 50% disappearance of the peak corresponding to the intact molecule (t1/2) was observed after ca. 80 hours. All derivatives were subjected to DPPH free radical scavenging assay and they exhibited activities quite higher than silibinin.
Moreover, the solubility in water of silibinin and its dimers as well as their ability to react with reactive oxygen species (ROS) were determined by estimating their second order rate constant with singlet oxygen (1O2) and hydroxyl radical (HO∙) in solution. This data were obtained in the laboratories of Prof. Marcello Brigante during my experience work in his research team at the University Blaise Pascal, Institute of Chemistry of Clermont-Ferrand (France). Solubility experiments indicate that dimers were completely dissolved (0.1 mg in 10 mL) in water and solubility can be estimated to be ≥ 19.5 µM corresponding to > 20 mg/L.
Reactivity between silibinin and dimers with 1O2 and HO∙ was determined by use of Rose Bengal (RB) and hydrogen peroxide as respective ROS sources. For this purpose, 545 nm centered excitation of RB and laser flash photolysis (LFP) experiments were coupled with a kinetic competition approach. Dimers reactivity toward singlet oxygen results to be close to the value determined for silibinin, or about 35% lower. Second order rate constant fare in the same order of magnitude reported in literature for molecules with similar structure. Morales and co-workers8 reported a reactivity ranging from 2.4 to 13.4 × 107 M-1s-1 for flavonoid derivative such as quercetin and morin. Estimation of second order rate constant reactivity with HO∙ indicates that some dimers showed a second order rate constant ≥ 1.5 × 1010 M–1s–1. Wang and co-workers (9) investigated the reactivity of hydroxyl radical with phenolic compounds in order to estimate their anti-oxidative ability using aqueous pulse radiolysis. The value of 1.5 × 1010 M–1s–1 was found for quercetin that is close to those estimates for green tea polyphenols. Interestingly, Husain at al.10 reported that reactivity of flavonoids toward photo-generated hydroxyl radical increases with the number of hydroxyl groups in the aromatic ring.
References
1 Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2012, 75, 311.
2 Gažák, R.; Walterová, D.; Křen, V. Curr. Med. Chem. 2007, 14, 315.
3 Napolitano, J. G.; Lankin, D. C.; Graf, T. N.; Friesen, J. B.; Chen, S-N.; McAlpine, J. B.; Oberlies, N. H.; Pauli, G. F. J. Org. Chem. 2013, 78, 2827.
4 Zhan, T.; Digel, M.; Küch, E.-M. J. Cell. Biochem. 2011, 112, 849 and references therein.
5 Zarrelli, A.; Romanucci, V.; Tuccillo, C.; Federico, A.; Loguercio, C.; Gravante, R.; Di Fabio, G. Bioorg. Med. Chem. Lett. 2014, 24, 5147.
6 Romanucci, V.; Gravante, R.; Di Marino, C.; Iuliano, M.; De Tommaso, G.; Caruso, T.; Zarrelli, A.; Di Fabio, G. submitted for publication.
7 Gravante, R .; Romanucci, V.; Cimafonte, M.; Di Marino, C.; Mailhot, G.; Brigante, M.; Zarrelli, A.; Di Fabio, G. submitted for publication.
8 Morales, J.; Günther, G.; Zanocco, A. L.; Lemp, E. PLoS One 2012, 7, e40548.
9 Wang, W. F.; Luo, J. S.; Yao, D.; Lian, Z. R.; Zhang, J. S.; Lin, N. Y. Radiat. Phys. Chem. 1993, 42, 985.
10 Rafat Husain, S.; Cillard, J.; Cillard, P. Phytochemistry 1987, 26, 2489
Phosphate-Linked Silibinin dimers (PLSd): Synthesis and Radical Scanvenger Behavior
No full textPolyphenols are active compounds of the medicinal plants widely distributed in nature. Despite the few and common biosynthetic origins, polyphenols encompass many subclasses of structurally different entities with a variety of pharmacological properties. Many studies suggests that the mechanisms by which plant polyphenols
exert their protective actions against various diseases, in part are due to their redox properties. Silibinin belongs to flavonolignan class and is a major component (approximately 30%) of the Silymarin complex extracted from milk thistle [Silybum marianum (L.) Gaertn. Carduus marianus L., Asteraceae]. Silibinin exists as a mixture of two diastereomers: Silybin A and Silybin B. Silibinin has long been studied for a large variety of pharmacological properties ranging from its antioxidant activity to neuroprotective and antiviral activities. Unfortunately, its in vivo applications are rather hampered by its very low bioavailability mainly due to low water solubility. In an attempt to improve its biological properties and facilitate the in vivo applications, we have developed an efficient strategy for the synthesis of Silibinin modified namely Phosphate-Linked Silibinin dimers (PLSd) in which the Silibinin monomer units are linked by phosphodiester bond (Figure). Exploiting the selective protection of Silibinin’s hydroxyl groups, we carried out a synthetic approach using the phosphoramidite chemistry. Water solubility of dimers, radical scavenger activity as well as their ability to react with reactive oxygen species (ROS) were determined. In particular, dimers reactivity with 1O2 and HO∙ was determined by use of Rose Bengal (RB) and hydrogen peroxide (H2O2) as respective ROS sources. For this purpose, laser flash photolysis (LFP) experiments were coupled with a kinetic competition approach. In addition to scavenging activity, the serum stability and cytoprotective (X/XO assay on HepG2 cells) behavior of dimers were evaluated
New dimers and trimers of the silibinin: synthesis, radical scavenger properties and beyond.
No full textPolyphenols are active compounds of the medicinal plants widely distributed in nature. Despite the few and common biosynthetic origins, polyphenols encompass many subclasses of structurally different entities with a variety of pharmacological properties. Many studies suggest that the mechanisms by which plant polyphenols exert their protective actions against various diseases, are in part due to their redox properties.1Silibinin belongs to flavonolignan class, it is a major component of the Silymarin complex extracted from the milk thistle (Silybum marianum). Silibinin has long been studied for its large variety of pharmacological properties ranging from the antioxidant activity to neuroprotective and antiviral activities.
In order to expand the repertoire of the modified Silibinins with high molecular diversity and good water solubility, here, we present a new and efficient method for the synthesis of dimers and trimers of the Silibinin, in which the monomer units are linked by phosphodiester bond Exploiting the selective protection of the Silibinin hydroxyl groups, we carried out a new synthetic approach using the well-established phosphoramidite chemistry. Aiming at the discovery of new pharmacological activities of these molecules, the water solubility, the
radical scavenger activity by DPPH test, as well as, their ability to scavenge different reactive oxygen species (1O2 and HO●) have been studied. Additionally, the serum stability and
cytoprotective behaviour (X/XO assay on HepG2 cells) of dimers have been evaluated. The combination of both striking antioxidant ability and high water solubility, makes these molecules, promising synthetic metabolites for future therapeutic applications
Corrado Cagli. Transatlantic bridges, 1938-1947
No full textIn the 1930s the young Italian artist, Corrado Cagli was a rising star of the Scuola Romana, supported by the Fascist regime despite being both Jewish and a homosexual. Following the Racial Laws, he fled first to Paris, and then to the USA, where he remained until 1947. Raffaele Bedarida’s new book, Corrado Cagli – La pittura, l’esilio, l’America (1938-1947) Donzelli Editore, 2018 (soon to be translated into English by CPL Editions), focuses on Cagli’s American exile.
While examining Cagli in the context of the artistic and intellectual migration from Europe to the US, Bedarida provides valuable new insight into the specific plight of this Italian Jewish artist, once championed by Fascism and into the complexities of the use of art for cultural diplomacy.
The author combines biography, cultural history, and critical analysis in exploring a decisive period in the life and work of a painter whose complex personality and non-signature style, defy classifications. The book also provides thought-provoking and nuanced arguments on the ideologically based ostracism that Cagli encountered upon returning to Italy in the immediate aftermath of the war. Because of his past as a former regime-endorsed artist, his recent American success, his participation in the liberation of Europe from Nazi-Fascism with the American army, and Jewish exile, Cagli simply did not fit into any of the faction of Italy’s post-war heated cultural disputes.
Based on extensive original research and written with brio, Bedarida’s book is an essential contribution to a growing field of studies that examine how, by welcoming artist and intellectuals in flight from Nazi-Fascism, the United States had been given what Will Norman has called “custodianship for a civilization.
Proceedings of the LREC 2020 workshop on Resources and Techniques for User and Author Profiling in Abusive Language (ResT-UP 2020)
No full textThis volume documents the Proceedings of the 1st Workshop on Resources and Techniques for User and Author Profiling in Abusive Language (ResT-UP), held online on 12 May 2020 as part of the LREC 2020 conference (International Conference on Language Resources and Evaluation).
The workshop aimed at bringing together researchers and scholars working on author profiling and automatic detection of abusive language on the Web, e.g., cyberbullying or hate speech, with a twofold objective: improving the existing LRs, e.g., datasets, corpora, lexicons, and sharing ideas on stylometry techniques and features needed for profile information extraction and classification. ResT-UP targeted Profiling scholars and research groups, experts in Statistic and Stylistic Analysis of texts as well as computational linguists who investigate author profile and personality both in short texts (social media posts, blog texts and email) and in long texts (such as pamphlets, (fake) news and political documents). ReST-UP represented an opportunity to share profiling experiments with the scientific community and to show automatic detection techniques of abusive language on the Web. Despite the cancellation of LREC 2020 due to the COVID-19 international emergency, ResT-UP was organized online on Microsoft Teams on May 12th 2020 and the programme included three oral presentations and featured an invited talk by Paolo Rosso. ResT-UP was attended by about fifty representatives of academic and industrial organisations
- …
