Francesco Peri - Academia.edu (original) (raw)
Papers by Francesco Peri
Tetrahedron, 1997
Calix[4]arenes 4 and calix[5]arenes 6 functionalized at the methylene bridge are synthesized star... more Calix[4]arenes 4 and calix[5]arenes 6 functionalized at the methylene bridge are synthesized starting from benzaldehydes 1. diphenylmethanes 2 and formaldehyde or 2.6-dihydroxymethylphenols 5 respectively. 1H NMR analyses of macrocycles 4 and 6 as well as crystal structure of the calix[5]arene 6by are reported.
Journal of Chromatography A, 1998
A new class of tetraamidic selectors with arms derived from l-phenylalanine and spaced by a pheno... more A new class of tetraamidic selectors with arms derived from l-phenylalanine and spaced by a phenolic template was synthesized. These chiral compounds were used as stationary phases for analytical gas chromatographic resolution of racemic mixtures of volatile amino acid derivatives; 1H NMR titration experiments were also performed. The experimental gas chromatographic and 1H NMR data collected support the hypothesis of a cooperation of the two chiral arms in binding and recognition of amino acidic substrates.
Febs Journal, 2007
α-Conotoxins from marine snails are known to be selective and potent competitive antagonists of n... more α-Conotoxins from marine snails are known to be selective and potent competitive antagonists of nicotinic acetylcholine receptors. Here we describe the purification, structural features and activity of two novel toxins, SrIA and SrIB, isolated from Conus spurius collected in the Yucatan Channel, Mexico. As determined by direct amino acid and cDNA nucleotide sequencing, the toxins are peptides containing 18 amino acid residues with the typical 4/7-type framework but with completely novel sequences. Therefore, their actions (and that of a synthetic analog, [γ15E]SrIB) were compared to those exerted by the α4/7-conotoxin EI from Conus ermineus, used as a control. Their target specificity was evaluated by the patch-clamp technique in mammalian cells expressing α1β1γδ, α4β2 and α3β4 nicotinic acetylcholine receptors. At high concentrations (10 µm), the peptides SrIA, SrIB and [γ15E]SrIB showed weak blocking effects only on α4β2 and α1β1γδ subtypes, but EI also strongly blocked α3β4 receptors. In contrast to this blocking effect, the new peptides and EI showed a remarkable potentiation of α1β1γδ and α4β2 nicotinic acetylcholine receptors if briefly (2–15 s) applied at concentrations several orders of magnitude lower (EC50, 1.78 and 0.37 nm, respectively). These results suggest not only that the novel α-conotoxins and EI can operate as nicotinic acetylcholine receptor inhibitors, but also that they bind both α1β1γδ and α4β2 nicotinic acetylcholine receptors with very high affinity and increase their intrinsic cholinergic response. Their unique properties make them excellent tools for studying the toxin–receptor interaction, as well as models with which to design highly specific therapeutic drugs.
Glia, 2008
Neuropathic pain remains a prevalent clinical problem because it is often poorly responsive to th... more Neuropathic pain remains a prevalent clinical problem because it is often poorly responsive to the currently used analgesics, thus it is crucial the identification of new potential targets and drugs. Recent evidence indicated that microglial cells in the spinal cord are critically involved in the development and maintenance of neuropathic pain, with a pivotal role of toll-like receptor 4 (TLR4). Binding of an endogenous ligand to TLR4 might be considered an important step in the regulation of microglia activity in pain facilitation, suggesting that a mechanism aimed to inhibit such a binding could be effective against neuropathic pain. We have synthesized new ligands to TLR4 with antagonistic activity. In the present work we evaluated the efficacy of the most potent TLR4 antagonist synthesized by us (FP-1), administered in mice with painful neuropathy. The repeated treatment of neuropathic mice with FP-1 (5–10 mg/kg, i.p.) evoked a relief of both thermal hyperalgesia and mechanical allodynia, whereas the administration of the highest dose to TLR4 knockout neuropathic mice revealed that in the absence of TLR4 receptor, the compound lost its efficacy. As consequence of TLR4 binding, the repeated treatment with FP-1 prevented the activation of the transcription factor NF-kB and the TNFα overproduction in the spinal cord. Together, our findings support the previous evidence indicative for a contribution of glial TLR4 to the initiation of neuropathic pain, suggest it as potential innovative target to treat this debilitating disease, and propose FP-1 as lead compound for the development of new effective drugs. © 2008 Wiley-Liss, Inc.
Chemical Communications, 2002
Bioorganic & Medicinal Chemistry, 2006
A mimetic of Lipid A with a β-N(OMe) glycosidic linkage, four linear C-14 hydrophobic chains and ... more A mimetic of Lipid A with a β-N(OMe) glycosidic linkage, four linear C-14 hydrophobic chains and without phosphate groups has been prepared together with its β-O-linked analogue. Both these molecules were active in inhibiting the inflammatory action of Escherichia coli lipid A on MT2 macrophages in a dose-dependent manner, while they were completely devoid of inflammatory activity.A novel lipid A mimetic with a methoxyamino glycosidic linkage presents antagonist activity against bacterial LPS.
Monatshefte Fur Chemie, 2002
The polyfunctionality and conformational rigidity of carbohydrates make this class of compounds ... more The polyfunctionality and conformational rigidity of carbohydrates make this class of compounds ideal scaffolds for the production of sortiments1 of bioactive compounds. Examples of carbohydrate-derived peptidomimetics of biological interest, such as somatostatin agonists and integrin antagonists, are presented. In order to have access to solid phase supported sortiments of compounds, orthogonally protected or unprotected carbohydrates were linked to polymers and reacted in the solid phase employing different regioselective strategies. Original bicyclic and tricyclic glycidic scaffolds were easily obtained starting from natural sugars such as D-arabinose and D-fructose. Manipulation of these conformationally blocked compounds afforded different carbohydrate-based derivatives, among which azidoacids are useful precursors of β-turn peptidomimetics.
Advances in Carbohydrate Chemistry and Biochemistry, 2007
This chapter discusses the interest in generating neoglycoconjugates of different types and repor... more This chapter discusses the interest in generating neoglycoconjugates of different types and reports on the different methods that permit the conjugation of the sugar, with or without spacers, to different aglycons. It is well recognized that glycoconjugates, and in particular glycopeptides and glycoproteins, act as mediators of an enormous variety of cellular events. With respect to structural diversity, they have the capacity to far exceed proteins and nucleic acids as the agents encoding information for specific molecular recognition, and they act as determinants of protein folding, stability, and pharmacokinetics. A current chemoselective approach to neoglycopeptides involves the assembly of multiepitopic glycoconjugates bearing clustered Tn antigen as synthetic anticancer vaccines. Inclusion of oligosacharides or polysaccharides in cell membrane models, such as lipid monolayers or liposomes, provides a basis for understanding the mechanisms that govern specific recognition phenomena. A G4 PAMAM dendrimer conjugate has been synthesized and in vivo studies have demonstrated its ability to protect against the experimental infection by influenza AX-31 H3N2 virus in mice. It is found that the chemoselective synthesis of neoglycoconjugates has benefitted from the techniques developed for the assembly of protein mimics, starting from unprotected fragment peptides.
European Journal of Organic Chemistry, 2006
Chemical Communications, 2000
Journal of Carbohydrate Chemistry, 2003
d‐Glucose derivatives bearing an anomeric thiophenyl group and orthogonally protections on second... more d‐Glucose derivatives bearing an anomeric thiophenyl group and orthogonally protections on secondary hydroxyl groups were linked to solid supports (PS/DV polymer, tentagel resin) through an ester bond on C‐6. It was investigated the possibility to remove orthogonally protecting groups and functionalize selectively the free hydroxyls groups and the anomeric carbon of sugars in solid phase.
Angewandte Chemie-international Edition, 2007
Journal of The Chemical Society-perkin Transactions 1, 2002
ABSTRACT
Bioorganic & Medicinal Chemistry, 2006
A bicyclic scaffold derived from the natural monosaccharide d-glucose, and possessing several div... more A bicyclic scaffold derived from the natural monosaccharide d-glucose, and possessing several diversity sites, was linked to various resins through the primary (C-6) hydroxyl and decorated on the solid phase: the hydroxyl group at C-4 was functionalized as ester, ether, and carbamate, the amino group in the second cycle (C-3′ position) was functionalized as amide, sulfonamide, and ureido- and thioureido-derivatives. The compounds synthesized on the solid phase were tested for their antiproliferative activity on tumor cell lines.
Chemical Communications, 2000
ABSTRACT Bicyclic amino acids derived from the natural sugars D-arabinofuranose and D-fructofuran... more ABSTRACT Bicyclic amino acids derived from the natural sugars D-arabinofuranose and D-fructofuranose have been synthesised; their ability to induce a turn conformation in peptides has been exploited in the preparation of a cyclic RGD loop mimetic.
Comptes Rendus Chimie, 2003
Chemistry-a European Journal, 2004
Rigid macrocyclic scaffolds based on carbohydrates have potential for the display of recognition ... more Rigid macrocyclic scaffolds based on carbohydrates have potential for the display of recognition groups with defined 3D structure and may have application in bioorganic and supramolecular chemistry. A series of water soluble macrocyclic structures containing two saccharide units was synthesised by ring closing metathesis of allyl and pentenyl glycosides derived from glucuronic acid. The 3D structure of the constrained systems was explored by NMR and computational methods. CD spectra were also recorded. On the basis of experimental observations we suggest that the carbohydrate presentation is constrained into a U-shape for the smaller ring size but can access an S-shape arrangement in the larger macrocycle. As an extension it is shown that the larger macrocycle displayed phenomena similar to b-cyclodextrin (b-CD). The binding of 8-anilino-1-naphthalenesulfonate (ANS) to b-CD is detectable by reversal of quenching of the ANS emission spectrum and a similar reversal of quenching was observed when this macrocycle was added to a solution of ANS; this was further supported by NMR. Furthermore molecular modelling suggests that the macrocyclic scaffolding has potential for the development of peptidomimetics.
Current Organic Synthesis, 2005
ABSTRACT Recent efforts in the use of carbohydrates as scaffolds for the production of bioactive ... more ABSTRACT Recent efforts in the use of carbohydrates as scaffolds for the production of bioactive compounds are reported. Orthogonally protected and solid phase supported monosaccharides for the production of libraries, exploiting the combinatorial approach by derivatisation of each hydroxyl group with different pharmacophores, are described. Example of peptidomimetics synthesised on a carbohydrate skeleton orienting proper amino acid residues, are also reported. In order to increase the conformational rigidity of the sugar templates, a variety of original bicyclic or policyclic polyfunctionalised structures have been synthesised from carbohydrates. Same of them have spiro or condensed bicyclic structures, others include one or more sugars in a macrocyclic framework or in cyclopeptides in order to induce bioactive peptide loops.
Bioconjugate Chemistry, 2001
The C-saccharide analogue of the GalNAc (Tn epitope) has been covalently linked to the T cell epi... more The C-saccharide analogue of the GalNAc (Tn epitope) has been covalently linked to the T cell epitope peptide 328-340 OVA using a chemoselective convergent synthetic approach. In this way, a nonhydrolyzable synthetic vaccine was obtained composed by a B epitope conjugated to a T cell epitope. This compound was tested in a proliferation assay with spleen cells from DO11.10 mice. The molecule was recognized by transgenic T cells although at a slightly lower efficiency if compared with the reference peptide OVA. An additional experiment with dendritic cells fixed with glutaraldehyde shows that the glycopeptide can bind to extracellular MHC molecules without need of internalization and processing and that the C-glycoside part does not interfere with TCR recognition. These observations constitute an important starting point for the use of this molecule as vaccine against the Tn-expressing TA3-Ha mouse mammary carcinoma.
Chemical Communications, 2004
Tetrahedron, 1997
Calix[4]arenes 4 and calix[5]arenes 6 functionalized at the methylene bridge are synthesized star... more Calix[4]arenes 4 and calix[5]arenes 6 functionalized at the methylene bridge are synthesized starting from benzaldehydes 1. diphenylmethanes 2 and formaldehyde or 2.6-dihydroxymethylphenols 5 respectively. 1H NMR analyses of macrocycles 4 and 6 as well as crystal structure of the calix[5]arene 6by are reported.
Journal of Chromatography A, 1998
A new class of tetraamidic selectors with arms derived from l-phenylalanine and spaced by a pheno... more A new class of tetraamidic selectors with arms derived from l-phenylalanine and spaced by a phenolic template was synthesized. These chiral compounds were used as stationary phases for analytical gas chromatographic resolution of racemic mixtures of volatile amino acid derivatives; 1H NMR titration experiments were also performed. The experimental gas chromatographic and 1H NMR data collected support the hypothesis of a cooperation of the two chiral arms in binding and recognition of amino acidic substrates.
Febs Journal, 2007
α-Conotoxins from marine snails are known to be selective and potent competitive antagonists of n... more α-Conotoxins from marine snails are known to be selective and potent competitive antagonists of nicotinic acetylcholine receptors. Here we describe the purification, structural features and activity of two novel toxins, SrIA and SrIB, isolated from Conus spurius collected in the Yucatan Channel, Mexico. As determined by direct amino acid and cDNA nucleotide sequencing, the toxins are peptides containing 18 amino acid residues with the typical 4/7-type framework but with completely novel sequences. Therefore, their actions (and that of a synthetic analog, [γ15E]SrIB) were compared to those exerted by the α4/7-conotoxin EI from Conus ermineus, used as a control. Their target specificity was evaluated by the patch-clamp technique in mammalian cells expressing α1β1γδ, α4β2 and α3β4 nicotinic acetylcholine receptors. At high concentrations (10 µm), the peptides SrIA, SrIB and [γ15E]SrIB showed weak blocking effects only on α4β2 and α1β1γδ subtypes, but EI also strongly blocked α3β4 receptors. In contrast to this blocking effect, the new peptides and EI showed a remarkable potentiation of α1β1γδ and α4β2 nicotinic acetylcholine receptors if briefly (2–15 s) applied at concentrations several orders of magnitude lower (EC50, 1.78 and 0.37 nm, respectively). These results suggest not only that the novel α-conotoxins and EI can operate as nicotinic acetylcholine receptor inhibitors, but also that they bind both α1β1γδ and α4β2 nicotinic acetylcholine receptors with very high affinity and increase their intrinsic cholinergic response. Their unique properties make them excellent tools for studying the toxin–receptor interaction, as well as models with which to design highly specific therapeutic drugs.
Glia, 2008
Neuropathic pain remains a prevalent clinical problem because it is often poorly responsive to th... more Neuropathic pain remains a prevalent clinical problem because it is often poorly responsive to the currently used analgesics, thus it is crucial the identification of new potential targets and drugs. Recent evidence indicated that microglial cells in the spinal cord are critically involved in the development and maintenance of neuropathic pain, with a pivotal role of toll-like receptor 4 (TLR4). Binding of an endogenous ligand to TLR4 might be considered an important step in the regulation of microglia activity in pain facilitation, suggesting that a mechanism aimed to inhibit such a binding could be effective against neuropathic pain. We have synthesized new ligands to TLR4 with antagonistic activity. In the present work we evaluated the efficacy of the most potent TLR4 antagonist synthesized by us (FP-1), administered in mice with painful neuropathy. The repeated treatment of neuropathic mice with FP-1 (5–10 mg/kg, i.p.) evoked a relief of both thermal hyperalgesia and mechanical allodynia, whereas the administration of the highest dose to TLR4 knockout neuropathic mice revealed that in the absence of TLR4 receptor, the compound lost its efficacy. As consequence of TLR4 binding, the repeated treatment with FP-1 prevented the activation of the transcription factor NF-kB and the TNFα overproduction in the spinal cord. Together, our findings support the previous evidence indicative for a contribution of glial TLR4 to the initiation of neuropathic pain, suggest it as potential innovative target to treat this debilitating disease, and propose FP-1 as lead compound for the development of new effective drugs. © 2008 Wiley-Liss, Inc.
Chemical Communications, 2002
Bioorganic & Medicinal Chemistry, 2006
A mimetic of Lipid A with a β-N(OMe) glycosidic linkage, four linear C-14 hydrophobic chains and ... more A mimetic of Lipid A with a β-N(OMe) glycosidic linkage, four linear C-14 hydrophobic chains and without phosphate groups has been prepared together with its β-O-linked analogue. Both these molecules were active in inhibiting the inflammatory action of Escherichia coli lipid A on MT2 macrophages in a dose-dependent manner, while they were completely devoid of inflammatory activity.A novel lipid A mimetic with a methoxyamino glycosidic linkage presents antagonist activity against bacterial LPS.
Monatshefte Fur Chemie, 2002
The polyfunctionality and conformational rigidity of carbohydrates make this class of compounds ... more The polyfunctionality and conformational rigidity of carbohydrates make this class of compounds ideal scaffolds for the production of sortiments1 of bioactive compounds. Examples of carbohydrate-derived peptidomimetics of biological interest, such as somatostatin agonists and integrin antagonists, are presented. In order to have access to solid phase supported sortiments of compounds, orthogonally protected or unprotected carbohydrates were linked to polymers and reacted in the solid phase employing different regioselective strategies. Original bicyclic and tricyclic glycidic scaffolds were easily obtained starting from natural sugars such as D-arabinose and D-fructose. Manipulation of these conformationally blocked compounds afforded different carbohydrate-based derivatives, among which azidoacids are useful precursors of β-turn peptidomimetics.
Advances in Carbohydrate Chemistry and Biochemistry, 2007
This chapter discusses the interest in generating neoglycoconjugates of different types and repor... more This chapter discusses the interest in generating neoglycoconjugates of different types and reports on the different methods that permit the conjugation of the sugar, with or without spacers, to different aglycons. It is well recognized that glycoconjugates, and in particular glycopeptides and glycoproteins, act as mediators of an enormous variety of cellular events. With respect to structural diversity, they have the capacity to far exceed proteins and nucleic acids as the agents encoding information for specific molecular recognition, and they act as determinants of protein folding, stability, and pharmacokinetics. A current chemoselective approach to neoglycopeptides involves the assembly of multiepitopic glycoconjugates bearing clustered Tn antigen as synthetic anticancer vaccines. Inclusion of oligosacharides or polysaccharides in cell membrane models, such as lipid monolayers or liposomes, provides a basis for understanding the mechanisms that govern specific recognition phenomena. A G4 PAMAM dendrimer conjugate has been synthesized and in vivo studies have demonstrated its ability to protect against the experimental infection by influenza AX-31 H3N2 virus in mice. It is found that the chemoselective synthesis of neoglycoconjugates has benefitted from the techniques developed for the assembly of protein mimics, starting from unprotected fragment peptides.
European Journal of Organic Chemistry, 2006
Chemical Communications, 2000
Journal of Carbohydrate Chemistry, 2003
d‐Glucose derivatives bearing an anomeric thiophenyl group and orthogonally protections on second... more d‐Glucose derivatives bearing an anomeric thiophenyl group and orthogonally protections on secondary hydroxyl groups were linked to solid supports (PS/DV polymer, tentagel resin) through an ester bond on C‐6. It was investigated the possibility to remove orthogonally protecting groups and functionalize selectively the free hydroxyls groups and the anomeric carbon of sugars in solid phase.
Angewandte Chemie-international Edition, 2007
Journal of The Chemical Society-perkin Transactions 1, 2002
ABSTRACT
Bioorganic & Medicinal Chemistry, 2006
A bicyclic scaffold derived from the natural monosaccharide d-glucose, and possessing several div... more A bicyclic scaffold derived from the natural monosaccharide d-glucose, and possessing several diversity sites, was linked to various resins through the primary (C-6) hydroxyl and decorated on the solid phase: the hydroxyl group at C-4 was functionalized as ester, ether, and carbamate, the amino group in the second cycle (C-3′ position) was functionalized as amide, sulfonamide, and ureido- and thioureido-derivatives. The compounds synthesized on the solid phase were tested for their antiproliferative activity on tumor cell lines.
Chemical Communications, 2000
ABSTRACT Bicyclic amino acids derived from the natural sugars D-arabinofuranose and D-fructofuran... more ABSTRACT Bicyclic amino acids derived from the natural sugars D-arabinofuranose and D-fructofuranose have been synthesised; their ability to induce a turn conformation in peptides has been exploited in the preparation of a cyclic RGD loop mimetic.
Comptes Rendus Chimie, 2003
Chemistry-a European Journal, 2004
Rigid macrocyclic scaffolds based on carbohydrates have potential for the display of recognition ... more Rigid macrocyclic scaffolds based on carbohydrates have potential for the display of recognition groups with defined 3D structure and may have application in bioorganic and supramolecular chemistry. A series of water soluble macrocyclic structures containing two saccharide units was synthesised by ring closing metathesis of allyl and pentenyl glycosides derived from glucuronic acid. The 3D structure of the constrained systems was explored by NMR and computational methods. CD spectra were also recorded. On the basis of experimental observations we suggest that the carbohydrate presentation is constrained into a U-shape for the smaller ring size but can access an S-shape arrangement in the larger macrocycle. As an extension it is shown that the larger macrocycle displayed phenomena similar to b-cyclodextrin (b-CD). The binding of 8-anilino-1-naphthalenesulfonate (ANS) to b-CD is detectable by reversal of quenching of the ANS emission spectrum and a similar reversal of quenching was observed when this macrocycle was added to a solution of ANS; this was further supported by NMR. Furthermore molecular modelling suggests that the macrocyclic scaffolding has potential for the development of peptidomimetics.
Current Organic Synthesis, 2005
ABSTRACT Recent efforts in the use of carbohydrates as scaffolds for the production of bioactive ... more ABSTRACT Recent efforts in the use of carbohydrates as scaffolds for the production of bioactive compounds are reported. Orthogonally protected and solid phase supported monosaccharides for the production of libraries, exploiting the combinatorial approach by derivatisation of each hydroxyl group with different pharmacophores, are described. Example of peptidomimetics synthesised on a carbohydrate skeleton orienting proper amino acid residues, are also reported. In order to increase the conformational rigidity of the sugar templates, a variety of original bicyclic or policyclic polyfunctionalised structures have been synthesised from carbohydrates. Same of them have spiro or condensed bicyclic structures, others include one or more sugars in a macrocyclic framework or in cyclopeptides in order to induce bioactive peptide loops.
Bioconjugate Chemistry, 2001
The C-saccharide analogue of the GalNAc (Tn epitope) has been covalently linked to the T cell epi... more The C-saccharide analogue of the GalNAc (Tn epitope) has been covalently linked to the T cell epitope peptide 328-340 OVA using a chemoselective convergent synthetic approach. In this way, a nonhydrolyzable synthetic vaccine was obtained composed by a B epitope conjugated to a T cell epitope. This compound was tested in a proliferation assay with spleen cells from DO11.10 mice. The molecule was recognized by transgenic T cells although at a slightly lower efficiency if compared with the reference peptide OVA. An additional experiment with dendritic cells fixed with glutaraldehyde shows that the glycopeptide can bind to extracellular MHC molecules without need of internalization and processing and that the C-glycoside part does not interfere with TCR recognition. These observations constitute an important starting point for the use of this molecule as vaccine against the Tn-expressing TA3-Ha mouse mammary carcinoma.
Chemical Communications, 2004