The Experts below are selected from a list of 261 Experts worldwide ranked by ideXlab platform
Sergio Cossu - One of the best experts on this subject based on the ideXlab platform.
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Rational Design, Synthesis, Characterization and Evaluation of Iodinated 4,4'-Bipyridines as New Transthyretin Fibrillogenesis Inhibitors.
Molecules (Basel Switzerland), 2020Co-Authors: Alessandro Dessì, Emmanuel Aubert, Paola Peluso, Roberto Dallocchio, Robin Weiss, Giuseppina Andreotti, Mariateresa Allocca, Patrick Pale, Victor Mamane, Sergio CossuAbstract:The 3,3′,5,5′-tetrachloro-2-iodo-4,4′-bipyridine structure is proposed as a novel chemical scaffold for the design of new transthyretin (TTR) fibrillogenesis inhibitors. In the frame of a proof-of-principle exploration, four chiral 3,3′,5,5′-tetrachloro-2-iodo-2′-substituted-4,4′- bipyridines were rationally designed and prepared from a simple trihalopyridine in three steps, including a Cu-catalysed Finkelstein Reaction to introduce iodine atoms on the heteroaromatic scaffold, and a Pd-catalysed coupling Reaction to install the 2′-substituent. The corresponding racemates, along with other five chiral 4,4′-bipyridines containing halogens as substituents, were enantioseparated by high-performance liquid chromatography in order to obtain pure enantiomer pairs. All stereoisomers were tested against the amyloid fibril formation (FF) of wild type (WT)-TTR and two mutant variants, V30M and Y78F, in acid mediated aggregation experiments. Among the 4,4′-bipyridine derivatives, interesting inhibition activity was obtained for both enantiomers of the 3,3′,5,5′-tetrachloro-2′-(4-hydroxyphenyl)-2-iodo-4,4′-bipyridine. In silico docking studies were carried out in order to explore possible binding modes of the 4,4′-bipyridine derivatives into the TTR. The gained results point out the importance of the right combination of H-bond sites and the presence of iodine as halogen-bond donor. Both experimental and theoretical evidences pave the way for the utilization of the iodinated 4,4′-bipyridine core as template to design new promising inhibitors of TTR amyloidogenesis.
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Rational Design, Synthesis, Characterization and Evaluation of Iodinated 4,4′-Bipyridines as New Transthyretin Fibrillogenesis Inhibitors
Molecules, 2020Co-Authors: Alessandro Dessì, Emmanuel Aubert, Paola Peluso, Roberto Dallocchio, Robin Weiss, Giuseppina Andreotti, Mariateresa Allocca, Patrick Pale, Victor Mamane, Sergio CossuAbstract:The 3,3 ,5,5-tetrachloro-2-iodo-4,4-bipyridine structure is proposed as a novel chemical scaffold for the design of new transthyretin (TTR) fibrillogenesis inhibitors. In the frame of a proof-of-principle exploration, four chiral 3,3 ,5,5-tetrachloro-2-iodo-2-substituted-4,4-bipyridines were rationally designed and prepared from a simple trihalopyridine in three steps, including a Cu-catalysed Finkelstein Reaction to introduce iodine atoms on the heteroaromatic scaffold, and a Pd-catalysed coupling Reaction to install the 2-substituent. The corresponding racemates, along with other five chiral 4,4-bipyridines containing halogens as substituents, were enantioseparated by high-performance liquid chromatography in order to obtain pure enantiomer pairs. All stereoisomers were tested against the amyloid fibril formation (FF) of wild type (WT)-TTR and two mutant variants, V30M and Y78F, in acid mediated aggregation experiments. Among the 4,4-bipyridine derivatives, interesting inhibition activity was obtained for both enantiomers of the 3,3 ,5,5-tetrachloro-2-(4-hydroxyphenyl)-2-iodo-4,4-bipyridine. In silico docking studies were carried out in order to explore possible binding modes of the 4,4-bipyridine derivatives into the TTR. The gained results point out the importance of the right combination of H-bond sites and the presence of iodine as halogen-bond donor. Both experimental and theoretical evidences pave the way for the utilization of the iodinated 4,4-bipyridine core as template to design new promising inhibitors of TTR amyloidogenesis.
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Chiral Hexahalogenated 4,4′-Bipyridines
The Journal of organic chemistry, 2016Co-Authors: Victor Mamane, Emmanuel Aubert, Sergio Cossu, Paola Peluso, Patrick PaleAbstract:The preparation of 27 isomers of chiral hexahalogeno-4,4′-bipyridines by means of two complementary methods is described. The first one is convergent and based on the LDA-induced 4,4′-dimerization of trihalopyridines, whereas the second method is divergent and achieved through regioselective halogenation Reactions of 4,4′-bipyridine-2,2′-diones. Iodine in 2,2′-positions of the 4,4′-bipyridines was introduced by a copper-catalyzed Finkelstein Reaction (Buchwald procedure) performed on 2,2′-dibromo derivatives. Selected compounds of this new family of atropisomeric 4,4′-bipyridines were enantioseparated by high performance liquid chromatography on chiral stationary phases, and the absolute configurations of the separated enantiomers were assigned by using X-ray diffraction analysis. The latter revealed that various halogen bond types are responsible for crystal cohesion.
Paola Peluso - One of the best experts on this subject based on the ideXlab platform.
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Rational Design, Synthesis, Characterization and Evaluation of Iodinated 4,4'-Bipyridines as New Transthyretin Fibrillogenesis Inhibitors.
Molecules (Basel Switzerland), 2020Co-Authors: Alessandro Dessì, Emmanuel Aubert, Paola Peluso, Roberto Dallocchio, Robin Weiss, Giuseppina Andreotti, Mariateresa Allocca, Patrick Pale, Victor Mamane, Sergio CossuAbstract:The 3,3′,5,5′-tetrachloro-2-iodo-4,4′-bipyridine structure is proposed as a novel chemical scaffold for the design of new transthyretin (TTR) fibrillogenesis inhibitors. In the frame of a proof-of-principle exploration, four chiral 3,3′,5,5′-tetrachloro-2-iodo-2′-substituted-4,4′- bipyridines were rationally designed and prepared from a simple trihalopyridine in three steps, including a Cu-catalysed Finkelstein Reaction to introduce iodine atoms on the heteroaromatic scaffold, and a Pd-catalysed coupling Reaction to install the 2′-substituent. The corresponding racemates, along with other five chiral 4,4′-bipyridines containing halogens as substituents, were enantioseparated by high-performance liquid chromatography in order to obtain pure enantiomer pairs. All stereoisomers were tested against the amyloid fibril formation (FF) of wild type (WT)-TTR and two mutant variants, V30M and Y78F, in acid mediated aggregation experiments. Among the 4,4′-bipyridine derivatives, interesting inhibition activity was obtained for both enantiomers of the 3,3′,5,5′-tetrachloro-2′-(4-hydroxyphenyl)-2-iodo-4,4′-bipyridine. In silico docking studies were carried out in order to explore possible binding modes of the 4,4′-bipyridine derivatives into the TTR. The gained results point out the importance of the right combination of H-bond sites and the presence of iodine as halogen-bond donor. Both experimental and theoretical evidences pave the way for the utilization of the iodinated 4,4′-bipyridine core as template to design new promising inhibitors of TTR amyloidogenesis.
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Rational Design, Synthesis, Characterization and Evaluation of Iodinated 4,4′-Bipyridines as New Transthyretin Fibrillogenesis Inhibitors
Molecules, 2020Co-Authors: Alessandro Dessì, Emmanuel Aubert, Paola Peluso, Roberto Dallocchio, Robin Weiss, Giuseppina Andreotti, Mariateresa Allocca, Patrick Pale, Victor Mamane, Sergio CossuAbstract:The 3,3 ,5,5-tetrachloro-2-iodo-4,4-bipyridine structure is proposed as a novel chemical scaffold for the design of new transthyretin (TTR) fibrillogenesis inhibitors. In the frame of a proof-of-principle exploration, four chiral 3,3 ,5,5-tetrachloro-2-iodo-2-substituted-4,4-bipyridines were rationally designed and prepared from a simple trihalopyridine in three steps, including a Cu-catalysed Finkelstein Reaction to introduce iodine atoms on the heteroaromatic scaffold, and a Pd-catalysed coupling Reaction to install the 2-substituent. The corresponding racemates, along with other five chiral 4,4-bipyridines containing halogens as substituents, were enantioseparated by high-performance liquid chromatography in order to obtain pure enantiomer pairs. All stereoisomers were tested against the amyloid fibril formation (FF) of wild type (WT)-TTR and two mutant variants, V30M and Y78F, in acid mediated aggregation experiments. Among the 4,4-bipyridine derivatives, interesting inhibition activity was obtained for both enantiomers of the 3,3 ,5,5-tetrachloro-2-(4-hydroxyphenyl)-2-iodo-4,4-bipyridine. In silico docking studies were carried out in order to explore possible binding modes of the 4,4-bipyridine derivatives into the TTR. The gained results point out the importance of the right combination of H-bond sites and the presence of iodine as halogen-bond donor. Both experimental and theoretical evidences pave the way for the utilization of the iodinated 4,4-bipyridine core as template to design new promising inhibitors of TTR amyloidogenesis.
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Chiral Hexahalogenated 4,4′-Bipyridines
The Journal of organic chemistry, 2016Co-Authors: Victor Mamane, Emmanuel Aubert, Sergio Cossu, Paola Peluso, Patrick PaleAbstract:The preparation of 27 isomers of chiral hexahalogeno-4,4′-bipyridines by means of two complementary methods is described. The first one is convergent and based on the LDA-induced 4,4′-dimerization of trihalopyridines, whereas the second method is divergent and achieved through regioselective halogenation Reactions of 4,4′-bipyridine-2,2′-diones. Iodine in 2,2′-positions of the 4,4′-bipyridines was introduced by a copper-catalyzed Finkelstein Reaction (Buchwald procedure) performed on 2,2′-dibromo derivatives. Selected compounds of this new family of atropisomeric 4,4′-bipyridines were enantioseparated by high performance liquid chromatography on chiral stationary phases, and the absolute configurations of the separated enantiomers were assigned by using X-ray diffraction analysis. The latter revealed that various halogen bond types are responsible for crystal cohesion.
Emmanuel Aubert - One of the best experts on this subject based on the ideXlab platform.
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Rational Design, Synthesis, Characterization and Evaluation of Iodinated 4,4'-Bipyridines as New Transthyretin Fibrillogenesis Inhibitors.
Molecules (Basel Switzerland), 2020Co-Authors: Alessandro Dessì, Emmanuel Aubert, Paola Peluso, Roberto Dallocchio, Robin Weiss, Giuseppina Andreotti, Mariateresa Allocca, Patrick Pale, Victor Mamane, Sergio CossuAbstract:The 3,3′,5,5′-tetrachloro-2-iodo-4,4′-bipyridine structure is proposed as a novel chemical scaffold for the design of new transthyretin (TTR) fibrillogenesis inhibitors. In the frame of a proof-of-principle exploration, four chiral 3,3′,5,5′-tetrachloro-2-iodo-2′-substituted-4,4′- bipyridines were rationally designed and prepared from a simple trihalopyridine in three steps, including a Cu-catalysed Finkelstein Reaction to introduce iodine atoms on the heteroaromatic scaffold, and a Pd-catalysed coupling Reaction to install the 2′-substituent. The corresponding racemates, along with other five chiral 4,4′-bipyridines containing halogens as substituents, were enantioseparated by high-performance liquid chromatography in order to obtain pure enantiomer pairs. All stereoisomers were tested against the amyloid fibril formation (FF) of wild type (WT)-TTR and two mutant variants, V30M and Y78F, in acid mediated aggregation experiments. Among the 4,4′-bipyridine derivatives, interesting inhibition activity was obtained for both enantiomers of the 3,3′,5,5′-tetrachloro-2′-(4-hydroxyphenyl)-2-iodo-4,4′-bipyridine. In silico docking studies were carried out in order to explore possible binding modes of the 4,4′-bipyridine derivatives into the TTR. The gained results point out the importance of the right combination of H-bond sites and the presence of iodine as halogen-bond donor. Both experimental and theoretical evidences pave the way for the utilization of the iodinated 4,4′-bipyridine core as template to design new promising inhibitors of TTR amyloidogenesis.
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Rational Design, Synthesis, Characterization and Evaluation of Iodinated 4,4′-Bipyridines as New Transthyretin Fibrillogenesis Inhibitors
Molecules, 2020Co-Authors: Alessandro Dessì, Emmanuel Aubert, Paola Peluso, Roberto Dallocchio, Robin Weiss, Giuseppina Andreotti, Mariateresa Allocca, Patrick Pale, Victor Mamane, Sergio CossuAbstract:The 3,3 ,5,5-tetrachloro-2-iodo-4,4-bipyridine structure is proposed as a novel chemical scaffold for the design of new transthyretin (TTR) fibrillogenesis inhibitors. In the frame of a proof-of-principle exploration, four chiral 3,3 ,5,5-tetrachloro-2-iodo-2-substituted-4,4-bipyridines were rationally designed and prepared from a simple trihalopyridine in three steps, including a Cu-catalysed Finkelstein Reaction to introduce iodine atoms on the heteroaromatic scaffold, and a Pd-catalysed coupling Reaction to install the 2-substituent. The corresponding racemates, along with other five chiral 4,4-bipyridines containing halogens as substituents, were enantioseparated by high-performance liquid chromatography in order to obtain pure enantiomer pairs. All stereoisomers were tested against the amyloid fibril formation (FF) of wild type (WT)-TTR and two mutant variants, V30M and Y78F, in acid mediated aggregation experiments. Among the 4,4-bipyridine derivatives, interesting inhibition activity was obtained for both enantiomers of the 3,3 ,5,5-tetrachloro-2-(4-hydroxyphenyl)-2-iodo-4,4-bipyridine. In silico docking studies were carried out in order to explore possible binding modes of the 4,4-bipyridine derivatives into the TTR. The gained results point out the importance of the right combination of H-bond sites and the presence of iodine as halogen-bond donor. Both experimental and theoretical evidences pave the way for the utilization of the iodinated 4,4-bipyridine core as template to design new promising inhibitors of TTR amyloidogenesis.
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Chiral Hexahalogenated 4,4′-Bipyridines
The Journal of organic chemistry, 2016Co-Authors: Victor Mamane, Emmanuel Aubert, Sergio Cossu, Paola Peluso, Patrick PaleAbstract:The preparation of 27 isomers of chiral hexahalogeno-4,4′-bipyridines by means of two complementary methods is described. The first one is convergent and based on the LDA-induced 4,4′-dimerization of trihalopyridines, whereas the second method is divergent and achieved through regioselective halogenation Reactions of 4,4′-bipyridine-2,2′-diones. Iodine in 2,2′-positions of the 4,4′-bipyridines was introduced by a copper-catalyzed Finkelstein Reaction (Buchwald procedure) performed on 2,2′-dibromo derivatives. Selected compounds of this new family of atropisomeric 4,4′-bipyridines were enantioseparated by high performance liquid chromatography on chiral stationary phases, and the absolute configurations of the separated enantiomers were assigned by using X-ray diffraction analysis. The latter revealed that various halogen bond types are responsible for crystal cohesion.
Alessandro Dessì - One of the best experts on this subject based on the ideXlab platform.
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Rational Design, Synthesis, Characterization and Evaluation of Iodinated 4,4'-Bipyridines as New Transthyretin Fibrillogenesis Inhibitors.
Molecules (Basel Switzerland), 2020Co-Authors: Alessandro Dessì, Emmanuel Aubert, Paola Peluso, Roberto Dallocchio, Robin Weiss, Giuseppina Andreotti, Mariateresa Allocca, Patrick Pale, Victor Mamane, Sergio CossuAbstract:The 3,3′,5,5′-tetrachloro-2-iodo-4,4′-bipyridine structure is proposed as a novel chemical scaffold for the design of new transthyretin (TTR) fibrillogenesis inhibitors. In the frame of a proof-of-principle exploration, four chiral 3,3′,5,5′-tetrachloro-2-iodo-2′-substituted-4,4′- bipyridines were rationally designed and prepared from a simple trihalopyridine in three steps, including a Cu-catalysed Finkelstein Reaction to introduce iodine atoms on the heteroaromatic scaffold, and a Pd-catalysed coupling Reaction to install the 2′-substituent. The corresponding racemates, along with other five chiral 4,4′-bipyridines containing halogens as substituents, were enantioseparated by high-performance liquid chromatography in order to obtain pure enantiomer pairs. All stereoisomers were tested against the amyloid fibril formation (FF) of wild type (WT)-TTR and two mutant variants, V30M and Y78F, in acid mediated aggregation experiments. Among the 4,4′-bipyridine derivatives, interesting inhibition activity was obtained for both enantiomers of the 3,3′,5,5′-tetrachloro-2′-(4-hydroxyphenyl)-2-iodo-4,4′-bipyridine. In silico docking studies were carried out in order to explore possible binding modes of the 4,4′-bipyridine derivatives into the TTR. The gained results point out the importance of the right combination of H-bond sites and the presence of iodine as halogen-bond donor. Both experimental and theoretical evidences pave the way for the utilization of the iodinated 4,4′-bipyridine core as template to design new promising inhibitors of TTR amyloidogenesis.
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Rational Design, Synthesis, Characterization and Evaluation of Iodinated 4,4′-Bipyridines as New Transthyretin Fibrillogenesis Inhibitors
Molecules, 2020Co-Authors: Alessandro Dessì, Emmanuel Aubert, Paola Peluso, Roberto Dallocchio, Robin Weiss, Giuseppina Andreotti, Mariateresa Allocca, Patrick Pale, Victor Mamane, Sergio CossuAbstract:The 3,3 ,5,5-tetrachloro-2-iodo-4,4-bipyridine structure is proposed as a novel chemical scaffold for the design of new transthyretin (TTR) fibrillogenesis inhibitors. In the frame of a proof-of-principle exploration, four chiral 3,3 ,5,5-tetrachloro-2-iodo-2-substituted-4,4-bipyridines were rationally designed and prepared from a simple trihalopyridine in three steps, including a Cu-catalysed Finkelstein Reaction to introduce iodine atoms on the heteroaromatic scaffold, and a Pd-catalysed coupling Reaction to install the 2-substituent. The corresponding racemates, along with other five chiral 4,4-bipyridines containing halogens as substituents, were enantioseparated by high-performance liquid chromatography in order to obtain pure enantiomer pairs. All stereoisomers were tested against the amyloid fibril formation (FF) of wild type (WT)-TTR and two mutant variants, V30M and Y78F, in acid mediated aggregation experiments. Among the 4,4-bipyridine derivatives, interesting inhibition activity was obtained for both enantiomers of the 3,3 ,5,5-tetrachloro-2-(4-hydroxyphenyl)-2-iodo-4,4-bipyridine. In silico docking studies were carried out in order to explore possible binding modes of the 4,4-bipyridine derivatives into the TTR. The gained results point out the importance of the right combination of H-bond sites and the presence of iodine as halogen-bond donor. Both experimental and theoretical evidences pave the way for the utilization of the iodinated 4,4-bipyridine core as template to design new promising inhibitors of TTR amyloidogenesis.
Martina H. Stenzel - One of the best experts on this subject based on the ideXlab platform.
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Enhanced delivery of the RAPTA-C macromolecular chemotherapeutic by conjugation to degradable polymeric micelles.
Biomacromolecules, 2013Co-Authors: Bianca M. Blunden, Martina H. StenzelAbstract:Macromolecular ruthenium complexes are a promising avenue to better and more selective chemotherapeutics. We have previously shown that RAPTA-C [RuCl2(p-cymene)(PTA)], with the water-soluble 1,3,5-phosphaadamantane (PTA) ligand, could be attached to a polymer moiety via nucleophilic substitution of an available iodide with an amide in the PTA ligand. To increase the cell uptake of this macromolecule, we designed an amphiphilic block copolymer capable of self-assembling into polymeric micelles. The block copolymer was prepared by ring-opening polymerization of d,l-lactide (3,6-dimethyl-1,4-dioxane-2,5-dione) using a RAFT agent with an additional hydroxyl functionality, followed by the RAFT copolymerization of 2-hydroxyethyl acrylate (HEA) and 2-chloroethyl methacrylate (CEMA). The Finkelstein Reaction and Reaction with PTA led to polymers that can readily react with the dimer of RuCl2(p-cymene) to create a macromolecular RAPTA-C drug. RAPTA-C conjugation, micellization, and subsequent cytotoxicity and cell...
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Enhanced Delivery of the RAPTA‑C Macromolecular Chemotherapeutic by Conjugation to Degradable Polymeric Micelles
2013Co-Authors: Bianca M. Blunden, Martina H. StenzelAbstract:Macromolecular ruthenium complexes are a promising avenue to better and more selective chemotherapeutics. We have previously shown that RAPTA-C [RuCl2(p-cymene)(PTA)], with the water-soluble 1,3,5-phosphaadamantane (PTA) ligand, could be attached to a polymer moiety via nucleophilic substitution of an available iodide with an amide in the PTA ligand. To increase the cell uptake of this macromolecule, we designed an amphiphilic block copolymer capable of self-assembling into polymeric micelles. The block copolymer was prepared by ring-opening polymerization of d,l-lactide (3,6-dimethyl-1,4-dioxane-2,5-dione) using a RAFT agent with an additional hydroxyl functionality, followed by the RAFT copolymerization of 2-hydroxyethyl acrylate (HEA) and 2-chloroethyl methacrylate (CEMA). The Finkelstein Reaction and Reaction with PTA led to polymers that can readily react with the dimer of RuCl2(p-cymene) to create a macromolecular RAPTA-C drug. RAPTA-C conjugation, micellization, and subsequent cytotoxicity and cell uptake of these polymeric moieties was tested on ovarian cancer A2780, A2780cis, and Ovcar-3 cell lines. Confocal microscopy images confirmed cell uptake of the micelles into the lysosome of the cells, indicative of an endocytic pathway. On average, a 10-fold increase in toxicity was found for the macromolecular drugs when compared to the RAPTA-C molecule. Furthermore, the cell uptake of ruthenium was analyzed and a significant increase was found for the micelles compared to RAPTA-C. Notably, micelles prepared from the polymer containing fewer HEA units had the highest cytotoxicity, the best cell uptake of ruthenium and were highly effective in suppressing the colony-forming ability of cells
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Macromolecular ruthenium complexes as anti-cancer agents
Polymer Chemistry, 2012Co-Authors: Bianca M. Blunden, Donald S. Thomas, Martina H. StenzelAbstract:Ruthenium complexes have shown promise as anti-cancer therapeutics. Among them, RAPTA-C [RuCl2(p-cymene)(PTA)] with the water-soluble 1,3,5-triaza-7-phosphaadamantane (PTA) ligand holds great promise as an alternative to platinum drugs. This paper explores synthetic pathways by which RAPTA-C can be attached to polymer moieties to create a water-soluble macromolecular drug that can potentially display an enhanced permeation and retention (EPR) effect. A reactive scaffold for RAPTA-C conjugation, poly(2-chloroethyl methacrylate) [PCEMA], was prepared via RAFT polymerisation. To increase the reactivity of the substrate, poly(2-iodoethyl methacrylate) [PIEMA] was prepared from PCEMA via the Finkelstein Reaction. Two pathways were employed to conjugate RAPTA-C to the polymer, either by attachment of PTA first followed by Reaction with the RuCl2(p-cymene) dimer, or by the direct conjugation of RAPTA-C to the polymer. Prior to the study with the polymer, both routes were tested using n-butyl iodide as a model compound. Several NMR experiments, namely 31P, 1H, [1H–31P] HMBC, [1H–13C] HMBC and [1H–15N] HMBC confirmed that both routes lead to the complete Reaction of n-butyl iodide and that only the desired product was obtained. However, the direct Reaction of RAPTA-C with the polymer required elevated temperature, which led to the loss of the p-cymene ligand. The two-step process at ambient temperature led to the successful formation of the product, albeit the amount of iodide reacted was now only 50% due to steric hindrance. Subsequently, a copolymer based on 2-hydroxypropyl methacrylamide [HPMA] and IEMA was synthesised. The two-step Reaction with PTA and RuCl2(p-cymene) dimer led to a water-soluble polymer with an intense orange colour, indicative of the pendant RAPTA-C complex. The monomodal molecular weight distribution monitored using UV-VIS detection of the macromolecular ruthenium complex confirmed drug attachment and indicates the absence of crosslinking events during drug conjugation. A cytotoxicity profile for the copolymer–RAPTA-C product was measured on the ovarian cancer cell line OVCAR-3 and compared with the profile of the lone RAPTA-C drug.