Maurizio Anzini | University of Siena / Università di Siena (original) (raw)
Papers by Maurizio Anzini
Farmaco (Società chimica italiana : 1989), 1993
The synthesis of 7-chloro-2,3-dihydro-2-(2-methoxyethyl)-1-methyl-5-phenyl- 1H-1,4-benzodiazepine... more The synthesis of 7-chloro-2,3-dihydro-2-(2-methoxyethyl)-1-methyl-5-phenyl- 1H-1,4-benzodiazepine (2) is described. While the metaclazepam-like compound 2 showed an affinity for benzodiazepine receptor central type (CBZRs) comparable to that of metaclazepam (1a), its intermediates bearing the exocyclic double bond resulted more active.
Journal of Medicinal Chemistry, 2004
3-Quinolinecarboxamides have been synthesized and evaluated for their binding to the human NK 1 r... more 3-Quinolinecarboxamides have been synthesized and evaluated for their binding to the human NK 1 receptor. Several secondary amide derivatives show NK1 receptor affinity in the picomolar range. The most active compound, hydroxymethylcarboxamide 3h showing an IC50 value in the subpicomolar range, behaved as an agonist of NK1 receptor in endothelial cell proliferation, inositol phosphate turnover, and NO-mediated cyclic GMP accumulation, thus proving it to be the first non-peptide NK1 receptor agonist showing very high potency.
Journal of Medicinal Chemistry, 2005
Novel arylpiperazine derivatives bearing lipophilic probes were designed, synthesized, and evalua... more Novel arylpiperazine derivatives bearing lipophilic probes were designed, synthesized, and evaluated for their potential ability to interact with the 5-hydroxytryptamine 3 (5-HT 3) receptor. Most of the new compounds show subnanomolar 5-HT 3 receptor affinity. Ester 6bc showing a picomolar K i value is one of the most potent 5-HT 3 receptor ligands so far synthesized. The structure-affinity relationship study suggests the existence of a certain degree of conformational freedom of the amino acid residues interacting with the substituents in positions 3 and 4 of the quipazine quinoline nucleus. Thus, the tacrine-related heterobivalent ligand 6o was designed in an attempt to capitalize on the evidence of such a steric tolerance. Compound 6o shows a nanomolar potency for both the 5-HT 3 receptor and the human AChE and represents the first example of a rationally designed high-affinity 5-HT 3 receptor ligand showing nanomolar AChE inhibitory activity. Finally, the computational analysis performed on compound 6o allowed the rationalization of the structure-energy determinants for AChE versus BuChE selectivity and revealed the existence of a subsite at the boundary of the 5-HT 3 receptor extracellular domain, which could represent a "peripheral" site similar to that evidenced in the AChE gorge.
Journal of Medicinal Chemistry, 2003
The structure-activity relationship studies on 2-quinolinecarboxamide peripheral benzodiazepine r... more The structure-activity relationship studies on 2-quinolinecarboxamide peripheral benzodiazepine receptor (PBR) ligands have been refined with the aim of using these ligands as carriers of radionuclides and boron atoms. Some new ligands show enhanced affinity and steroidogenic activity with respect to reference compound 1 and are interesting candidates for radiolabeling and PET studies. Moreover, carborane derivative 3q, representing the first example of PBR ligand bearing a carborane cage, can be useful to explore an alternative mechanism in BNCT.
Journal of Medicinal Chemistry, 1997
The synthesis and the biological evaluation of a series of novel pyrroloquinoxaline derivatives a... more The synthesis and the biological evaluation of a series of novel pyrroloquinoxaline derivatives are described. In binding studies several compounds proved to be potent and selective 5-HT 3 receptor ligands. The most active pyrroloquinoxalines, 11d and 11e, showed a subnanomolar affinity for 5-HT 3 receptor and were able to functionally discriminate the central and peripheral 5-HT 3 receptors, being agonists and antagonists, respectively. In functional studies ([ 14 C]guanidinium accumulation test in NG 108-15 cells, in vitro) most of the synthesized compounds showed clear-cut 5-HT 3 agonist properties. In in vivo studies on the von Bezold-Jarisch reflex test (a peripheral interaction model) the behavior of the tested compounds ranged from agonist to antagonist, while clear agonist properties were obtained with 12a on cortical acetylcholine release in freely moving rats. Pharmacokinetic studies with 11e and 12c indicate that the compounds easily cross the blood-brain barrier (BBB) after systemic administration with a brain/plasma ratio of 17.5 and 37.5, respectively. Thus compounds 11e and 12c represent the most potent central 5-HT 3 agonists identified to date that are able to cross the blood-brain barrier.
Current Topics in Medicinal Chemistry, 2010
The 5-HT(3) receptor (5-HT(3)R) occupies a special place among the serotonin receptor subtypes be... more The 5-HT(3) receptor (5-HT(3)R) occupies a special place among the serotonin receptor subtypes because it has been shown to be a ligand-gated ion channel, which is involved in a number of physiological functions and important pathologies. 5-HT(3)R antagonists have shown an outstanding efficacy in the control of the emesis induced by anticancer chemotherapy and few adverse side-effects, so as to revolutionize the treatment of nausea in cancer patients. This review covers the authors' work performed during the past decade in the development of 5-HT(3)R ligands belonging to the class of arylpiperazine derivatives related to quipazine (quipazine-like arylpiperazines, QLAs) and represents the extension of the review previously published in Current Topics in Medicinal Chemistry in 2002. The discussion is focused mainly on the most significant structure-affinity relationships emerged in the progress of the work and shows how the original ideas have evolved in the recent years.
Bioorganic & Medicinal Chemistry, 2002
The results of a comprehensive structure-affinity relationship study on the effect of the quatern... more The results of a comprehensive structure-affinity relationship study on the effect of the quaternization (i.e., N-methylation) of structurally different ligands in the classes of tropane and quinuclidine derivatives are described. This study shows that the effects of the quaternization of the basic nitrogen of these 5-HT(3) receptor ligands appear to be strictly structure-dependent suggesting that different binding modes are operative at 5-HT(3) receptor binding site. The different effect of the quaternization of the basic nitrogen of structurally different ligands were rationalized in terms of the interaction with the receptor by means of the combined use of experimental techniques (X-ray diffraction and NMR studies) and computational simulation studies.
Bioorganic & Medicinal Chemistry, 1996
The molecular structure and the dynamic behaviour of some potent 5-HT3 antagonists structurally r... more The molecular structure and the dynamic behaviour of some potent 5-HT3 antagonists structurally related to quipazine have been investigated by NMR spectroscopy and by computational methods in order to gain insight into the structure-activity relationships at a molecular level. The role of the different dynamic behaviour of these compounds in the binding to 5-HT3 receptors is discussed. A model of ligand-receptor interaction has been developed on the basis of molecular orbital calculations and on the reference ligands quipazine, ondansetron and LY278584. The interaction model proposed herein rationalizes the observed agonist-antagonist shift between quipazine and investigated compounds with the assumption of different but overlapping binding domains for antagonists and agonists at the 5-HT3 receptor.
Bioorganic & Medicinal Chemistry, 2005
A series of quipazine derivatives, previously synthesized to probe the 5-HT(3) receptor, was eval... more A series of quipazine derivatives, previously synthesized to probe the 5-HT(3) receptor, was evaluated for its potential interaction with serotonin transporter (SERT). Some of them show nanomolar affinity for the rodent SERT comparable to or slightly higher than quipazine or N-methylquipazine. Subsequently a candidate was selected on the basis of its SERT affinity and submitted to a molecular manipulation of the basic moiety. The structure-affinity relationships obtained provided information on the role of the fused benzene ring of quipazine in the interaction with the SERT binding site and on the stereoelectronic requirements for the interaction of both the heteroaromatic component and the basic moiety. Moreover, the comparison of the structure-affinity relationships obtained in the present work with those concerning the interaction of these heteroarylpiperazine derivatives with 5-HT3 receptor suggested some molecular determinants of the selectivity SERT/5HT3 receptor.
Bioorganic & Medicinal Chemistry, 2006
The previous exploration of the structure-affinity relationships concerning 4-phenyl-2-quinolinec... more The previous exploration of the structure-affinity relationships concerning 4-phenyl-2-quinolinecarboxamide peripheral benzodiazepine receptor (PBR) ligands 6 showed as an interesting result the importance of the presence of a chlorine atom in the methylene carbon at position 3 of the quinoline nucleus. The subnanomolar PBR affinity shown by N-benzyl-3-chloromethyl-Nmethyl-4-phenyl-2-quinolinecarboxamide (6b) suggested its chlorine atom to be replaced with other halogens in order to optimize the interaction of the quinolinecarboxamide derivatives with PBR and to develop suitable candidates for positron emission tomography (PET) or single photon emission computed tomography (SPECT) studies. The binding studies led to the discovery of fluoromethyl derivative 6a, which showed an IC 50 value of 0.11 nM and is, therefore, one of the most potent PBR ligands so far described. Fluoromethyl derivative 6a has been labeled with 11 C (t 1/2 = 20.4 min, b + = 99.8%) starting from the corresponding des-methyl precursor (14) using [ 11 C]CH 3 I in the presence of tetrabutylammonium hydroxide in DMF with a 35-40% radiochemical yield (corrected for decay) and 1.5 Ci/lmol of specific radioactivity. Ex vivo rat biodistribution and inhibition (following intravenous pre-administration of PK11195) studies showed that [ 11 C]6a rapidly and specifically accumulated in PBR-rich tissues such as heart, lung, kidney, spleen, and adrenal, and at a lower level in other peripheral organs and in the brain. The images obtained in mouse with small animal YAP-(S)PET essentially confirmed the result of the ex vivo biodistribution experiments. The biological data suggest that [ 11 C]6a is a promising radioligand for peripheral benzodiazepine receptor PET imaging in vivo.
Bioorganic & Medicinal Chemistry, 2011
The quinoline nucleus of the previously described 4-phenylquinoline-3-carboxamides NK 1 receptor ... more The quinoline nucleus of the previously described 4-phenylquinoline-3-carboxamides NK 1 receptor ligands 7 has been transformed into either substituted or azole-(i.e., triazole or tetrazole) fused pyridine moieties of compounds 9 and 10, respectively, in order to obtain NK 1 receptor ligands showing lower molecular weight or higher hydrophilicity. The program of molecular manipulations produced NK 1 receptor ligands showing affinity in the nanomolar range. In particular, 4-methyl-1-piperazinyl derivative 9j showed an IC 50 value of 4.8 nM and was proved to behave as a NK 1 antagonist blocking Sar 9-SP-sulfone induced proliferation and migration of microvascular endothelial cells. Therefore, compound 9j has been labeled with [ 11 C]CH 3 I (t 1/2 = 20.4 min, b + = 99.8%) starting from the corresponding des-methyl precursor 9i using with a radiochemical yield of about 10% (not decay corrected) and a specific radioactivity >1 Ci/lmol in order to be used as a radiotracer in next PET studies.
A small set of substituted 1,5-diarylpyrrole-3-acetic and-glyoxylic acid derivatives have been sy... more A small set of substituted 1,5-diarylpyrrole-3-acetic and-glyoxylic acid derivatives have been synthesized, and their cyclooxygenase (COX-1 and COX-2) inhibiting properties have been evaluated. Some compounds proved to be highly selective COX-2 inhibitors, and their affinity data have been rationalized through docking simulations in terms of interactions with a crystallographic model of the COX-2 binding site.
MedChemComm, 2018
A structure–affinity relationship study led to the discovery of 7h–j as novel 5-HT4 receptor liga... more A structure–affinity relationship study led to the discovery of 7h–j as novel 5-HT4 receptor ligands showing Ki values in the subnanomolar range.
Pharmaceutics, 2019
In order to evaluate the potential of a technology platform based on hyaluronan copolymers grafte... more In order to evaluate the potential of a technology platform based on hyaluronan copolymers grafted with propargylated ferulate fluorophores (HA-FA-Pg) in the development of drug delivery systems, the propargyl groups of HA-FA-Pg derivatives were employed with oleic acid (OA) or stearic acid (SA) residues across a biocompatible hexa(ethylene glycol) (HEG) spacer. The designed materials (i.e., HA-FA-HEG-OA or HA-FA-HEG-SA) showed clear-cut aggregation features in an aqueous environment, as confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM), generating nanoaggregate systems. In fact, HA-FA-HEG-OA and HA-FA-HEG-SA derivatives showed the property to create self-assembled cytocompatible nanostructured aggregates in water, thanks to the simultaneous presence of hydrophilic portions in the polymeric backbone, such as hyaluronic acid, and hydrophobic portions in the side chains. Furthermore, the designed materials interact with living cells showing a high ...
International Immunopharmacology, 2018
Selective cyclooxigenase (COX)-2 inhibitors were developed to prevent traditional non-steroidal a... more Selective cyclooxigenase (COX)-2 inhibitors were developed to prevent traditional non-steroidal anti-inflammatory drugs (tNSAIDs) gastro-intestinal adverse effects. VA692, a recently disclosed selective COX-2 inhibitor, structurally related to well-known marketed coxibs, showed anti-inflammatory, and anti-nociceptive properties. The aim of this study was to analyze the anti-inflammatory effect of VA692, in comparison with celecoxib. At this purpose we evaluated the pro-inflammatory cytokines and anti-oxidant enzymes gene expression, apoptosis and ROS production, and PGE release in chondrocytes (both primary cultures and immortalized T/C-28a2 cell line) treated with the two drugs. Furthermore, a proteomic analysis has been performed in T/C-28a2 cell line to evaluate modifications in their proteomic profile following drug treatment in presence of IL-1β. Our results demonstrated the anti-inflammatory effect of the novel synthesized VA692, and confirmed those of celecoxib, in counteracting the stimulus of IL-1β in both osteoarthritic (OA) chondrocytes and T/C-28a2 cell line. Furthermore, the data underlined the possible anti-apoptotic and anti-oxidant role of VA692, implying its regulation in superoxide anion production as indicated by the modulation of anti-oxidant enzymes. The proteomic analysis provides new information about the effect of VA692 on human T/C-28a2 intracellular proteome, demonstrating the usefulness of this approach in the identification and quantifications of several proteins. Modulation of some proteins such as Hsp90 and SOD by VA692 could explain its role in the therapeutic approach of OA. Based on our results, we can affirm that VA692 has more beneficial effect compared with celecoxib particularly regarding the modulation of oxidant/anti-oxidant system and proteome profile of human articular chondrocytes.
ChemMedChem, Jan 15, 2018
The enzyme Zmp1 is a zinc-peptidase having a critical role in M. tuberculosis pathogenicity. Here... more The enzyme Zmp1 is a zinc-peptidase having a critical role in M. tuberculosis pathogenicity. Here we describe the identification of a small set of Zmp1 inhibitors based on a novel 8-hydroxyquinoline-2-hydroxamate scaffold. Among the synthesized compounds, 1c was the most potent Zmp1 inhibitor known to date, and its binding mode was analysed both through kinetic studies and molecular modelling, identifying critical interactions of 1c with the zinc-ion and residues in the active site. Effect of 1c on intracellular Mycobacterium survival was assayed in J774 murine macrophages infected with M. tuberculosis H37Rv or M. bovis BCG and human monocyte-derived macrophages infected with M. tuberculosis H37Rv. Cytotoxicity and genotoxicity were also assessed. Overall, inhibitor 1c displayed interesting in vitro antitubercular properties worth of further investigation.
![Research paper thumbnail of Characterization of Quinoline Derivatives. II. 7-(4-Methyl-1-piperazinyl)-6H-[1]benzopyrano[3,4-c]quinoline](https://attachments.academia-assets.com/85732561/thumbnails/1.jpg)
](Acta Crystallographica Section C Crystal Structure Communications, 1998
![Research paper thumbnail of Characterization of Quinoline Derivatives. I. 6,7-Dihydro-8-(4-methyl-1-piperazinyl)[1]benzoxepino[4,5-c]quinoline 0.13-Hydrate](https://attachments.academia-assets.com/85732554/thumbnails/1.jpg)
](Acta Crystallographica Section C Crystal Structure Communications, 1997
This electronic document was scanned from an archival copy of material deposited to accompany a p... more This electronic document was scanned from an archival copy of material deposited to accompany a paper published in an IUCr journal. In many cases the only accessible copy was a microfilm of a poor-quality original.
Chirality, Jan 5, 2017
The capacity of nonsteroidal antiinflammatory drugs (NSAIDs) to prevent prostanoids biosynthesis ... more The capacity of nonsteroidal antiinflammatory drugs (NSAIDs) to prevent prostanoids biosynthesis through the inhibition of COX-2 enzyme is related to their structural backbone, based on the fusion of a cis-stilbene unit with a variety of heterocyclic and carbocyclic rings. By this route, a series of new selective COX-2 inhibitors was developed, by maintaining the 4-methylsulfone or 4-methylsulfonamide substituent on the phenyl moiety, essential for their activity. In this frame, two novel propyl sulfoxide derivatives were synthesized, which proved selective and sufficiently potent COX-2 inhibition activity when tested as racemates. In the present study, the use of a cellulose tris(3,5-dichlorophenylcarbamate)-based chiral stationary phase, in a polar-organic mode of elution, enabled the successful enantioseparation of the investigated compounds. The developed chromatography method reveals a useful tool of monitoring in view of a proper forthcoming enantioselective synthetic protocol...
Bioorganic & Medicinal Chemistry Letters, 2016
Farmaco (Società chimica italiana : 1989), 1993
The synthesis of 7-chloro-2,3-dihydro-2-(2-methoxyethyl)-1-methyl-5-phenyl- 1H-1,4-benzodiazepine... more The synthesis of 7-chloro-2,3-dihydro-2-(2-methoxyethyl)-1-methyl-5-phenyl- 1H-1,4-benzodiazepine (2) is described. While the metaclazepam-like compound 2 showed an affinity for benzodiazepine receptor central type (CBZRs) comparable to that of metaclazepam (1a), its intermediates bearing the exocyclic double bond resulted more active.
Journal of Medicinal Chemistry, 2004
3-Quinolinecarboxamides have been synthesized and evaluated for their binding to the human NK 1 r... more 3-Quinolinecarboxamides have been synthesized and evaluated for their binding to the human NK 1 receptor. Several secondary amide derivatives show NK1 receptor affinity in the picomolar range. The most active compound, hydroxymethylcarboxamide 3h showing an IC50 value in the subpicomolar range, behaved as an agonist of NK1 receptor in endothelial cell proliferation, inositol phosphate turnover, and NO-mediated cyclic GMP accumulation, thus proving it to be the first non-peptide NK1 receptor agonist showing very high potency.
Journal of Medicinal Chemistry, 2005
Novel arylpiperazine derivatives bearing lipophilic probes were designed, synthesized, and evalua... more Novel arylpiperazine derivatives bearing lipophilic probes were designed, synthesized, and evaluated for their potential ability to interact with the 5-hydroxytryptamine 3 (5-HT 3) receptor. Most of the new compounds show subnanomolar 5-HT 3 receptor affinity. Ester 6bc showing a picomolar K i value is one of the most potent 5-HT 3 receptor ligands so far synthesized. The structure-affinity relationship study suggests the existence of a certain degree of conformational freedom of the amino acid residues interacting with the substituents in positions 3 and 4 of the quipazine quinoline nucleus. Thus, the tacrine-related heterobivalent ligand 6o was designed in an attempt to capitalize on the evidence of such a steric tolerance. Compound 6o shows a nanomolar potency for both the 5-HT 3 receptor and the human AChE and represents the first example of a rationally designed high-affinity 5-HT 3 receptor ligand showing nanomolar AChE inhibitory activity. Finally, the computational analysis performed on compound 6o allowed the rationalization of the structure-energy determinants for AChE versus BuChE selectivity and revealed the existence of a subsite at the boundary of the 5-HT 3 receptor extracellular domain, which could represent a "peripheral" site similar to that evidenced in the AChE gorge.
Journal of Medicinal Chemistry, 2003
The structure-activity relationship studies on 2-quinolinecarboxamide peripheral benzodiazepine r... more The structure-activity relationship studies on 2-quinolinecarboxamide peripheral benzodiazepine receptor (PBR) ligands have been refined with the aim of using these ligands as carriers of radionuclides and boron atoms. Some new ligands show enhanced affinity and steroidogenic activity with respect to reference compound 1 and are interesting candidates for radiolabeling and PET studies. Moreover, carborane derivative 3q, representing the first example of PBR ligand bearing a carborane cage, can be useful to explore an alternative mechanism in BNCT.
Journal of Medicinal Chemistry, 1997
The synthesis and the biological evaluation of a series of novel pyrroloquinoxaline derivatives a... more The synthesis and the biological evaluation of a series of novel pyrroloquinoxaline derivatives are described. In binding studies several compounds proved to be potent and selective 5-HT 3 receptor ligands. The most active pyrroloquinoxalines, 11d and 11e, showed a subnanomolar affinity for 5-HT 3 receptor and were able to functionally discriminate the central and peripheral 5-HT 3 receptors, being agonists and antagonists, respectively. In functional studies ([ 14 C]guanidinium accumulation test in NG 108-15 cells, in vitro) most of the synthesized compounds showed clear-cut 5-HT 3 agonist properties. In in vivo studies on the von Bezold-Jarisch reflex test (a peripheral interaction model) the behavior of the tested compounds ranged from agonist to antagonist, while clear agonist properties were obtained with 12a on cortical acetylcholine release in freely moving rats. Pharmacokinetic studies with 11e and 12c indicate that the compounds easily cross the blood-brain barrier (BBB) after systemic administration with a brain/plasma ratio of 17.5 and 37.5, respectively. Thus compounds 11e and 12c represent the most potent central 5-HT 3 agonists identified to date that are able to cross the blood-brain barrier.
Current Topics in Medicinal Chemistry, 2010
The 5-HT(3) receptor (5-HT(3)R) occupies a special place among the serotonin receptor subtypes be... more The 5-HT(3) receptor (5-HT(3)R) occupies a special place among the serotonin receptor subtypes because it has been shown to be a ligand-gated ion channel, which is involved in a number of physiological functions and important pathologies. 5-HT(3)R antagonists have shown an outstanding efficacy in the control of the emesis induced by anticancer chemotherapy and few adverse side-effects, so as to revolutionize the treatment of nausea in cancer patients. This review covers the authors' work performed during the past decade in the development of 5-HT(3)R ligands belonging to the class of arylpiperazine derivatives related to quipazine (quipazine-like arylpiperazines, QLAs) and represents the extension of the review previously published in Current Topics in Medicinal Chemistry in 2002. The discussion is focused mainly on the most significant structure-affinity relationships emerged in the progress of the work and shows how the original ideas have evolved in the recent years.
Bioorganic & Medicinal Chemistry, 2002
The results of a comprehensive structure-affinity relationship study on the effect of the quatern... more The results of a comprehensive structure-affinity relationship study on the effect of the quaternization (i.e., N-methylation) of structurally different ligands in the classes of tropane and quinuclidine derivatives are described. This study shows that the effects of the quaternization of the basic nitrogen of these 5-HT(3) receptor ligands appear to be strictly structure-dependent suggesting that different binding modes are operative at 5-HT(3) receptor binding site. The different effect of the quaternization of the basic nitrogen of structurally different ligands were rationalized in terms of the interaction with the receptor by means of the combined use of experimental techniques (X-ray diffraction and NMR studies) and computational simulation studies.
Bioorganic & Medicinal Chemistry, 1996
The molecular structure and the dynamic behaviour of some potent 5-HT3 antagonists structurally r... more The molecular structure and the dynamic behaviour of some potent 5-HT3 antagonists structurally related to quipazine have been investigated by NMR spectroscopy and by computational methods in order to gain insight into the structure-activity relationships at a molecular level. The role of the different dynamic behaviour of these compounds in the binding to 5-HT3 receptors is discussed. A model of ligand-receptor interaction has been developed on the basis of molecular orbital calculations and on the reference ligands quipazine, ondansetron and LY278584. The interaction model proposed herein rationalizes the observed agonist-antagonist shift between quipazine and investigated compounds with the assumption of different but overlapping binding domains for antagonists and agonists at the 5-HT3 receptor.
Bioorganic & Medicinal Chemistry, 2005
A series of quipazine derivatives, previously synthesized to probe the 5-HT(3) receptor, was eval... more A series of quipazine derivatives, previously synthesized to probe the 5-HT(3) receptor, was evaluated for its potential interaction with serotonin transporter (SERT). Some of them show nanomolar affinity for the rodent SERT comparable to or slightly higher than quipazine or N-methylquipazine. Subsequently a candidate was selected on the basis of its SERT affinity and submitted to a molecular manipulation of the basic moiety. The structure-affinity relationships obtained provided information on the role of the fused benzene ring of quipazine in the interaction with the SERT binding site and on the stereoelectronic requirements for the interaction of both the heteroaromatic component and the basic moiety. Moreover, the comparison of the structure-affinity relationships obtained in the present work with those concerning the interaction of these heteroarylpiperazine derivatives with 5-HT3 receptor suggested some molecular determinants of the selectivity SERT/5HT3 receptor.
Bioorganic & Medicinal Chemistry, 2006
The previous exploration of the structure-affinity relationships concerning 4-phenyl-2-quinolinec... more The previous exploration of the structure-affinity relationships concerning 4-phenyl-2-quinolinecarboxamide peripheral benzodiazepine receptor (PBR) ligands 6 showed as an interesting result the importance of the presence of a chlorine atom in the methylene carbon at position 3 of the quinoline nucleus. The subnanomolar PBR affinity shown by N-benzyl-3-chloromethyl-Nmethyl-4-phenyl-2-quinolinecarboxamide (6b) suggested its chlorine atom to be replaced with other halogens in order to optimize the interaction of the quinolinecarboxamide derivatives with PBR and to develop suitable candidates for positron emission tomography (PET) or single photon emission computed tomography (SPECT) studies. The binding studies led to the discovery of fluoromethyl derivative 6a, which showed an IC 50 value of 0.11 nM and is, therefore, one of the most potent PBR ligands so far described. Fluoromethyl derivative 6a has been labeled with 11 C (t 1/2 = 20.4 min, b + = 99.8%) starting from the corresponding des-methyl precursor (14) using [ 11 C]CH 3 I in the presence of tetrabutylammonium hydroxide in DMF with a 35-40% radiochemical yield (corrected for decay) and 1.5 Ci/lmol of specific radioactivity. Ex vivo rat biodistribution and inhibition (following intravenous pre-administration of PK11195) studies showed that [ 11 C]6a rapidly and specifically accumulated in PBR-rich tissues such as heart, lung, kidney, spleen, and adrenal, and at a lower level in other peripheral organs and in the brain. The images obtained in mouse with small animal YAP-(S)PET essentially confirmed the result of the ex vivo biodistribution experiments. The biological data suggest that [ 11 C]6a is a promising radioligand for peripheral benzodiazepine receptor PET imaging in vivo.
Bioorganic & Medicinal Chemistry, 2011
The quinoline nucleus of the previously described 4-phenylquinoline-3-carboxamides NK 1 receptor ... more The quinoline nucleus of the previously described 4-phenylquinoline-3-carboxamides NK 1 receptor ligands 7 has been transformed into either substituted or azole-(i.e., triazole or tetrazole) fused pyridine moieties of compounds 9 and 10, respectively, in order to obtain NK 1 receptor ligands showing lower molecular weight or higher hydrophilicity. The program of molecular manipulations produced NK 1 receptor ligands showing affinity in the nanomolar range. In particular, 4-methyl-1-piperazinyl derivative 9j showed an IC 50 value of 4.8 nM and was proved to behave as a NK 1 antagonist blocking Sar 9-SP-sulfone induced proliferation and migration of microvascular endothelial cells. Therefore, compound 9j has been labeled with [ 11 C]CH 3 I (t 1/2 = 20.4 min, b + = 99.8%) starting from the corresponding des-methyl precursor 9i using with a radiochemical yield of about 10% (not decay corrected) and a specific radioactivity >1 Ci/lmol in order to be used as a radiotracer in next PET studies.
A small set of substituted 1,5-diarylpyrrole-3-acetic and-glyoxylic acid derivatives have been sy... more A small set of substituted 1,5-diarylpyrrole-3-acetic and-glyoxylic acid derivatives have been synthesized, and their cyclooxygenase (COX-1 and COX-2) inhibiting properties have been evaluated. Some compounds proved to be highly selective COX-2 inhibitors, and their affinity data have been rationalized through docking simulations in terms of interactions with a crystallographic model of the COX-2 binding site.
MedChemComm, 2018
A structure–affinity relationship study led to the discovery of 7h–j as novel 5-HT4 receptor liga... more A structure–affinity relationship study led to the discovery of 7h–j as novel 5-HT4 receptor ligands showing Ki values in the subnanomolar range.
Pharmaceutics, 2019
In order to evaluate the potential of a technology platform based on hyaluronan copolymers grafte... more In order to evaluate the potential of a technology platform based on hyaluronan copolymers grafted with propargylated ferulate fluorophores (HA-FA-Pg) in the development of drug delivery systems, the propargyl groups of HA-FA-Pg derivatives were employed with oleic acid (OA) or stearic acid (SA) residues across a biocompatible hexa(ethylene glycol) (HEG) spacer. The designed materials (i.e., HA-FA-HEG-OA or HA-FA-HEG-SA) showed clear-cut aggregation features in an aqueous environment, as confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM), generating nanoaggregate systems. In fact, HA-FA-HEG-OA and HA-FA-HEG-SA derivatives showed the property to create self-assembled cytocompatible nanostructured aggregates in water, thanks to the simultaneous presence of hydrophilic portions in the polymeric backbone, such as hyaluronic acid, and hydrophobic portions in the side chains. Furthermore, the designed materials interact with living cells showing a high ...
International Immunopharmacology, 2018
Selective cyclooxigenase (COX)-2 inhibitors were developed to prevent traditional non-steroidal a... more Selective cyclooxigenase (COX)-2 inhibitors were developed to prevent traditional non-steroidal anti-inflammatory drugs (tNSAIDs) gastro-intestinal adverse effects. VA692, a recently disclosed selective COX-2 inhibitor, structurally related to well-known marketed coxibs, showed anti-inflammatory, and anti-nociceptive properties. The aim of this study was to analyze the anti-inflammatory effect of VA692, in comparison with celecoxib. At this purpose we evaluated the pro-inflammatory cytokines and anti-oxidant enzymes gene expression, apoptosis and ROS production, and PGE release in chondrocytes (both primary cultures and immortalized T/C-28a2 cell line) treated with the two drugs. Furthermore, a proteomic analysis has been performed in T/C-28a2 cell line to evaluate modifications in their proteomic profile following drug treatment in presence of IL-1β. Our results demonstrated the anti-inflammatory effect of the novel synthesized VA692, and confirmed those of celecoxib, in counteracting the stimulus of IL-1β in both osteoarthritic (OA) chondrocytes and T/C-28a2 cell line. Furthermore, the data underlined the possible anti-apoptotic and anti-oxidant role of VA692, implying its regulation in superoxide anion production as indicated by the modulation of anti-oxidant enzymes. The proteomic analysis provides new information about the effect of VA692 on human T/C-28a2 intracellular proteome, demonstrating the usefulness of this approach in the identification and quantifications of several proteins. Modulation of some proteins such as Hsp90 and SOD by VA692 could explain its role in the therapeutic approach of OA. Based on our results, we can affirm that VA692 has more beneficial effect compared with celecoxib particularly regarding the modulation of oxidant/anti-oxidant system and proteome profile of human articular chondrocytes.
ChemMedChem, Jan 15, 2018
The enzyme Zmp1 is a zinc-peptidase having a critical role in M. tuberculosis pathogenicity. Here... more The enzyme Zmp1 is a zinc-peptidase having a critical role in M. tuberculosis pathogenicity. Here we describe the identification of a small set of Zmp1 inhibitors based on a novel 8-hydroxyquinoline-2-hydroxamate scaffold. Among the synthesized compounds, 1c was the most potent Zmp1 inhibitor known to date, and its binding mode was analysed both through kinetic studies and molecular modelling, identifying critical interactions of 1c with the zinc-ion and residues in the active site. Effect of 1c on intracellular Mycobacterium survival was assayed in J774 murine macrophages infected with M. tuberculosis H37Rv or M. bovis BCG and human monocyte-derived macrophages infected with M. tuberculosis H37Rv. Cytotoxicity and genotoxicity were also assessed. Overall, inhibitor 1c displayed interesting in vitro antitubercular properties worth of further investigation.
Acta Crystallographica Section C Crystal Structure Communications, 1998
Acta Crystallographica Section C Crystal Structure Communications, 1997
This electronic document was scanned from an archival copy of material deposited to accompany a p... more This electronic document was scanned from an archival copy of material deposited to accompany a paper published in an IUCr journal. In many cases the only accessible copy was a microfilm of a poor-quality original.
Chirality, Jan 5, 2017
The capacity of nonsteroidal antiinflammatory drugs (NSAIDs) to prevent prostanoids biosynthesis ... more The capacity of nonsteroidal antiinflammatory drugs (NSAIDs) to prevent prostanoids biosynthesis through the inhibition of COX-2 enzyme is related to their structural backbone, based on the fusion of a cis-stilbene unit with a variety of heterocyclic and carbocyclic rings. By this route, a series of new selective COX-2 inhibitors was developed, by maintaining the 4-methylsulfone or 4-methylsulfonamide substituent on the phenyl moiety, essential for their activity. In this frame, two novel propyl sulfoxide derivatives were synthesized, which proved selective and sufficiently potent COX-2 inhibition activity when tested as racemates. In the present study, the use of a cellulose tris(3,5-dichlorophenylcarbamate)-based chiral stationary phase, in a polar-organic mode of elution, enabled the successful enantioseparation of the investigated compounds. The developed chromatography method reveals a useful tool of monitoring in view of a proper forthcoming enantioselective synthetic protocol...
Bioorganic & Medicinal Chemistry Letters, 2016