Umberto Battisti | Virginia Commonwealth University (original) (raw)
Papers by Umberto Battisti
Journal of Chromatography A, 2016
Almost all Iridium(III) complexes employed both as dopants in PhOLEDs and as pharmaceuticals and ... more Almost all Iridium(III) complexes employed both as dopants in PhOLEDs and as pharmaceuticals and fluorescence bioprobes are racemic mixtures. In this study the single enantiomers of the most stable diastereomeric form fac-trans-N-N, bis[2-(4,6-difluorophenyl)pyridinato-C(2),N](picolinato)iridium(III) (FIrpic) were separated and analysed. The data obtained showed that the complex can be separated into stable optically active Λ and Δ isomers employing cellulose based chiral stationary phase both in normal and polar phase mode. Their chirality was confirmed and their absolute configuration assigned employing several methods (DFT and TDDFT calculations, CD and VCD). The CPL spectroscopy of the isolated enantiomers of FIrpic was also recorded due to its possible value in the OLEDs field. The chromatographic method was applied for a semipreparative purpose demonstrating that polar organic solvent chromatography (POSC) could be used to avoid the low-solubility issues associated with these Iridium(III) complexes. Finally, the chemical and stereochemical stability of the single isomers was evaluated under thermal stress by liquid chromatography coupled to high-resolution mass spectrometry (LC-QTOF) on both chiral and achiral columns. No racemization and/or isomerization was observed; however, the dissociation of the ancillary ligand was demonstrated employing LC-QTOF.
Journal of Chromatography A, 2016
A "heart-cut" two-dimensional a... more A "heart-cut" two-dimensional achiral-chiral liquid chromatography triple-quadrupole mass spectrometry method (LC-LC-MS/MS) was developed and coupled to in vivo cerebral microdialysis to evaluate the brain response to the chiral compound (±)-7-chloro-5-(3-furanyl)-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide ((±)-1), a potent positive allosteric modulator (PAM) of AMPA receptor. The method was successfully employed to evaluate also its stereoselective metabolism and in vitro biological activity. In particular, the LC achiral method developed, employs a pentafluorinated silica based column (Discovery HS-F5) to separate dopamine, acetylcholine, serotonin, (±)-1 and its two hepatic metabolites. In the "heart-cut" two-dimension achiral-chiral configuration, (±)-1 and (±)-1-d4 eluted from the achiral column (1st dimension), were transferred to a polysaccharide-based chiral column (2nd dimension, Chiralcel OD-RH) by using an automatic six-port valve. Single enantiomers of (±)-1 were separated and detected using electrospray positive ionization mode and quantified in selected reaction monitoring mode. The method was validated and showed good performance in terms of linearity, accuracy and precision. The new method employed showed several possible applications in the evaluation of: (a) brain response to neuroactive compounds by measuring variations in the brain extracellular levels of selected neurotransmitters and other biomarkers; (b) blood brain barrier penetration of drug candidates by measuring the free concentration of the drug in selected brain areas; (c) the presence of drug metabolites in the brain extracellular fluid that could prove very useful during drug discovery; (d) a possible stereoselective metabolization or blood brain barrier stereoselective crossing of chiral drugs. Finally, compared to the methods reported in the literature, this technique avoids the necessity of euthanizing an animal at each time point to measure drug concentration in whole brain tissue and provides continuous monitoring of extracellular concentrations of single chiral drug enantiomers along with its metabolites in specific brain regions at each selected time point for a desired period by using a single animal.
ACS chemical neuroscience, Jan 18, 2015
5-Arylbenzothiadiazine type compounds acting as positive allosteric modulators of AMPA receptor (... more 5-Arylbenzothiadiazine type compounds acting as positive allosteric modulators of AMPA receptor (AMPA-PAMs) have received particular attention in the last decade for their nootropic activity and lack of the excitotoxic side effects of direct agonists. Recently, our research group has published the synthesis and biological activity of 7-chloro-5-(3-furanyl)-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide (1), one of the most active benzothiadiazine-derived AMPA-PAMs in vitro to date. However, 1 exists as two stereolabile enantiomers, which rapidly racemise in physiological conditions and only one isomer is responsible for the pharmacological activity. In the present work, experiments carried out with rat liver microsomes show that 1 is converted by hepatic cytochrome P450 to the corresponding unsaturated derivative 2 and to the corresponding pharmacologically inactive benzenesulfonamide 3. Surprisingly, patch-clamp experiments reveal that 2 displays an activity comparable ...
![Research paper thumbnail of Efficient synthesis of 5,6-dihydro-8H-[1,2,4]thiadiazino[6,5,4-de]phenanthridine 4,4-dioxide and 5,6-dihydro-8H-[1,2,4]-thiadiazino[6,5,4-ij]thieno[2,3-c]quinoline 4,4-dioxide](https://attachments.academia-assets.com/47893580/thumbnails/1.jpg)
](Tetrahedron Letters, 2012
A new efficient and versatile synthesis to obtain different substituted 5,6-dihydro-8H-[1,2,4]thi... more A new efficient and versatile synthesis to obtain different substituted 5,6-dihydro-8H-[1,2,4]thiadiazino[6,5,4-de]phenanthridine 4,4-dioxide and 5,6-dihydro-8H-[1,2,4]-thiadiazino[6,5,4-ij]thieno[2,3c]quinolone 4,4-dioxide was developed. The four cyclic systems are achieved by a three-step synthesis proceeding under mild conditions in high yields.
![Research paper thumbnail of ChemInform Abstract: Efficient Synthesis of 5,6-Dihydro-8H-[1,2,4]thiadiazino[6,5,4-de]phenanthridine 4,4-Dioxide and 5,6-Dihydro-8H-[1,2,4]-thiadiazino[6,5,4-ij]thieno[2,3-c]quinoline 4,4-Dioxide](https://attachments.academia-assets.com/47893575/thumbnails/1.jpg)
](ChemInform, 2012
Efficient Synthesis of 5,6-Dihydro-8H-[1,2,4]thiadiazino[6,5,4-de]phenanthridine 4,4-Dioxide and ... more Efficient Synthesis of 5,6-Dihydro-8H-[1,2,4]thiadiazino[6,5,4-de]phenanthridine 4,4-Dioxide and 5,6-Dihydro-8H-[1,2,4]-thiadiazino[6,5,4-ij]thieno[2,3-c]quinoline 4,4-Dioxide. -The three-step synthesis of the title compounds is based on formation of key intermediates (III) and (VIII) from substrate (I) and boronic acids via Suzuki coupling and imine formation. -(BATTISTI, U. M.; CARROZZO, M. M.; CANNAZZA*, G.; BRAGHIROLI, D.; PARENTI, C.; BRASILI, L.; CITTI, C.; TROISI, L.; Tetrahedron Lett. 53 (2012) 9, 1122-1125, http://dx.doi.org/10.1016/j.tetlet.2011.12.091 ; Dip. Sci. Farm., Univ. Modena, I-41100 Modena, Italy; Eng.) -Mais 24-177
Tetrahedron Letters, 2012
ACS Medicinal Chemistry Letters, 2012
The potential therapeutic benefit of compounds able to activate AMPA receptors (AMPAr) has led to... more The potential therapeutic benefit of compounds able to activate AMPA receptors (AMPAr) has led to the search for new AMPAr positive modulators. On the basis of crystallographic data of the benzothiadiazines binding mode in the S1S2 GluA2 dimer interface, a set of 5-aryl-2,3dihydrobenzothiadiazine type compounds has been synthesized and tested. Electrophysiological results suggested that 5-heteroaryl substituents on the benzothiadiazine core like 3-furanyl and 3-thiophenyl dramatically enhance the activity as positive modulators of AMPAr with respect to IDRA21 and cyclothiazide. Mouse brain microdialysis studies have suggested that 7-chloro-5-(3-furyl)-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide crosses the blood−brain barrier after intraperitoneal injection. Biological results have been rationalized by a computational docking simulation that it has currently employed to design new AMPArpositive modulator candidates.
Journal of Chromatography A, 2016
Almost all Iridium(III) complexes employed both as dopants in PhOLEDs and as pharmaceuticals and ... more Almost all Iridium(III) complexes employed both as dopants in PhOLEDs and as pharmaceuticals and fluorescence bioprobes are racemic mixtures. In this study the single enantiomers of the most stable diastereomeric form fac-trans-N-N, bis[2-(4,6-difluorophenyl)pyridinato-C(2),N](picolinato)iridium(III) (FIrpic) were separated and analysed. The data obtained showed that the complex can be separated into stable optically active Λ and Δ isomers employing cellulose based chiral stationary phase both in normal and polar phase mode. Their chirality was confirmed and their absolute configuration assigned employing several methods (DFT and TDDFT calculations, CD and VCD). The CPL spectroscopy of the isolated enantiomers of FIrpic was also recorded due to its possible value in the OLEDs field. The chromatographic method was applied for a semipreparative purpose demonstrating that polar organic solvent chromatography (POSC) could be used to avoid the low-solubility issues associated with these Iridium(III) complexes. Finally, the chemical and stereochemical stability of the single isomers was evaluated under thermal stress by liquid chromatography coupled to high-resolution mass spectrometry (LC-QTOF) on both chiral and achiral columns. No racemization and/or isomerization was observed; however, the dissociation of the ancillary ligand was demonstrated employing LC-QTOF.
Journal of Chromatography A, 2016
A "heart-cut" two-dimensional achiral-chiral li... more A "heart-cut" two-dimensional achiral-chiral liquid chromatography triple-quadrupole mass spectrometry method (LC-LC-MS/MS) was developed and coupled to in vivo cerebral microdialysis to evaluate the brain response to the chiral compound (±)-7-chloro-5-(3-furanyl)-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide ((±)-1), a potent positive allosteric modulator (PAM) of AMPA receptor. The method was successfully employed to evaluate also its stereoselective metabolism and in vitro biological activity. In particular, the LC achiral method developed, employs a pentafluorinated silica based column (Discovery HS-F5) to separate dopamine, acetylcholine, serotonin, (±)-1 and its two hepatic metabolites. In the "heart-cut" two-dimension achiral-chiral configuration, (±)-1 and (±)-1-d4 eluted from the achiral column (1st dimension), were transferred to a polysaccharide-based chiral column (2nd dimension, Chiralcel OD-RH) by using an automatic six-port valve. Single enantiomers of (±)-1 were separated and detected using electrospray positive ionization mode and quantified in selected reaction monitoring mode. The method was validated and showed good performance in terms of linearity, accuracy and precision. The new method employed showed several possible applications in the evaluation of: (a) brain response to neuroactive compounds by measuring variations in the brain extracellular levels of selected neurotransmitters and other biomarkers; (b) blood brain barrier penetration of drug candidates by measuring the free concentration of the drug in selected brain areas; (c) the presence of drug metabolites in the brain extracellular fluid that could prove very useful during drug discovery; (d) a possible stereoselective metabolization or blood brain barrier stereoselective crossing of chiral drugs. Finally, compared to the methods reported in the literature, this technique avoids the necessity of euthanizing an animal at each time point to measure drug concentration in whole brain tissue and provides continuous monitoring of extracellular concentrations of single chiral drug enantiomers along with its metabolites in specific brain regions at each selected time point for a desired period by using a single animal.
European Journal of Medicinal Chemistry, 2016
Herein we report the synthesis and biological activity of new sigma receptor (σR) ligands obtaine... more Herein we report the synthesis and biological activity of new sigma receptor (σR) ligands obtained by combining different substituted five-membered heterocyclic rings with appropriate σR pharmacophoric amines. Radioligand binding assay, performed on guinea pig brain membranes, identified 25b (1-(1,4-dioxaspiro[4.5]decan-2-ylmethyl)-4-benzylpiperazine) as the most interesting compound of the series, displaying high affinity and selectivity for σ1R (pKiσ1 = 9.13; σ1/σ2 = 47). The ability of 25b to modulate the analgesic effect of the κ agonist (-)-U-50,488H and μ agonist morphine was evaluated in vivo by radiant heat tail-flick test. It exhibited anti-opioid effects on both κ and μ receptor-mediated analgesia, suggesting an agonistic behavior at σ1R. Docking studies were performed on the theoretical σ1R homology model. The present work represents a new starting point for the design of more potent and selective σ1R ligands.
Chirality, Sep 19, 2011
A stopped-flow bidimensional recycle HPLC (sf-BD-rHPLC) configuration has been used to investigat... more A stopped-flow bidimensional recycle HPLC (sf-BD-rHPLC) configuration has been used to investigate simultaneously the stereo and chemical stability of labile chiral compounds. The single enantiomers of a racemate can be separated on chiral column (first dimension) and each one can be trapped in the achiral column (second dimension) that works as reactor.By filling the achiral column with the appropriate aqueous buffers it is possible to evaluate the stability of the trapped enantiomer toward aqueous buffer itself. It was possible to recycle the reaction products formed in the chiral column (first dimension) where they are separated by a second six valve port. The reaction rate constants were calculated for the different processes occurred in the achiral column by means of corresponding peak areas. The method was applied to a pharmacological active compound: (±)7-chloro-5-ethyl-3-methyl-3,4-dihydro-2H-benzo[1,2,4]thiadiazine 1,1-dioxide ((±)-1) to evaluate enantiostability and hydrolysis in conditions similar to those of biological fluid. A classical batchwise kinetic method was used to calculate rate constants of hydrolysis and enantiomerization at the same temperature and in the same solvents used in sf-BD-rHPLC. The good agreement of the results obtained validate the novel procedure developed. Furthermore, the results generated off-line were used to determine the influence of solvents on the racemization of (±)-1.
ACS chemical neuroscience, Jan 18, 2015
5-Arylbenzothiadiazine type compounds acting as positive allosteric modulators of AMPA receptor (... more 5-Arylbenzothiadiazine type compounds acting as positive allosteric modulators of AMPA receptor (AMPA-PAMs) have received particular attention in the last decade for their nootropic activity and lack of the excitotoxic side effects of direct agonists. Recently, our research group has published the synthesis and biological activity of 7-chloro-5-(3-furanyl)-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide (1), one of the most active benzothiadiazine-derived AMPA-PAMs in vitro to date. However, 1 exists as two stereolabile enantiomers, which rapidly racemise in physiological conditions and only one isomer is responsible for the pharmacological activity. In the present work, experiments carried out with rat liver microsomes show that 1 is converted by hepatic cytochrome P450 to the corresponding unsaturated derivative 2 and to the corresponding pharmacologically inactive benzenesulfonamide 3. Surprisingly, patch-clamp experiments reveal that 2 displays an activity comparable ...
![Research paper thumbnail of Efficient synthesis of 5,6-dihydro-8H-[1,2,4]thiadiazino[6,5,4-de]phenanthridine 4,4-dioxide and 5,6-dihydro-8H-[1,2,4]-thiadiazino[6,5,4-ij]thieno[2,3-c]quinoline 4,4-dioxide](https://attachments.academia-assets.com/47808796/thumbnails/1.jpg)
](Tetrahedron Letters, 2012
A new efficient and versatile synthesis to obtain different substituted 5,6-dihydro-8H-[1,2,4]thi... more A new efficient and versatile synthesis to obtain different substituted 5,6-dihydro-8H-[1,2,4]thiadiazino[6,5,4-de]phenanthridine 4,4-dioxide and 5,6-dihydro-8H-[1,2,4]-thiadiazino[6,5,4-ij]thieno[2,3c]quinolone 4,4-dioxide was developed. The four cyclic systems are achieved by a three-step synthesis proceeding under mild conditions in high yields.
![Research paper thumbnail of ChemInform Abstract: Efficient Synthesis of 5,6-Dihydro-8H-[1,2,4]thiadiazino[6,5,4-de]phenanthridine 4,4-Dioxide and 5,6-Dihydro-8H-[1,2,4]-thiadiazino[6,5,4-ij]thieno[2,3-c]quinoline 4,4-Dioxide](https://attachments.academia-assets.com/47808792/thumbnails/1.jpg)
](ChemInform, 2012
Efficient Synthesis of 5,6-Dihydro-8H-[1,2,4]thiadiazino[6,5,4-de]phenanthridine 4,4-Dioxide and ... more Efficient Synthesis of 5,6-Dihydro-8H-[1,2,4]thiadiazino[6,5,4-de]phenanthridine 4,4-Dioxide and 5,6-Dihydro-8H-[1,2,4]-thiadiazino[6,5,4-ij]thieno[2,3-c]quinoline 4,4-Dioxide. -The three-step synthesis of the title compounds is based on formation of key intermediates (III) and (VIII) from substrate (I) and boronic acids via Suzuki coupling and imine formation. -(BATTISTI, U. M.; CARROZZO, M. M.; CANNAZZA*, G.; BRAGHIROLI, D.; PARENTI, C.; BRASILI, L.; CITTI, C.; TROISI, L.; Tetrahedron Lett. 53 (2012) 9, 1122-1125, http://dx.doi.org/10.1016/j.tetlet.2011.12.091 ; Dip. Sci. Farm., Univ. Modena, I-41100 Modena, Italy; Eng.) -Mais 24-177
Journal of Chromatography A, 2014
Development of an in vitro Liquid Chromatography-Mass Spectrometry method to evaluate stereo and ... more Development of an in vitro Liquid Chromatography-Mass Spectrometry method to evaluate stereo and chemical stability of new drug candidates employing immobilized artificial membrane column, Journal of Chromatography A (2014), http://dx.
Tetrahedron Letters, 2010
A simple and efficient synthetic path for N-1 or N-2 alkyl-substituted 2-aminobenzenesulfonamides... more A simple and efficient synthetic path for N-1 or N-2 alkyl-substituted 2-aminobenzenesulfonamides was developed based on regioselective reduction with NaBH3CN in different solvents.
European Journal of Organic Chemistry, 2015
ABSTRACT (1,3-Dioxan-4-yl)-substituted nucleoside analogues, higher homologues of antiviral and a... more ABSTRACT (1,3-Dioxan-4-yl)-substituted nucleoside analogues, higher homologues of antiviral and anticancer 1,3-dioxolanes, were prepared from the key intermediate (4-acetoxy-1,3-dioxan-2-yl)methyl benzoate and silylated bases. Glycosylation, carried out under Vorbrüggen conditions in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) as a catalyst, afforded the desired compounds with high stereoselectivity and regioselectivity, with only the desired β-anomeric N-1 pyrimidine and N-9 purin nucleosides being obtained. 1H NMR experiments established that the β-anomers were diequatorial, and this assignment was confirmed by single-crystal X-ray diffraction. Despite their structural similarities with natural nucleosides, none of the synthesized nucleosides showed antiviral activity.
Synlett, 2015
ABSTRACT 1,3-Dioxan-5-yl pyrimidine and purine nucleoside analogues were prepared following a new... more ABSTRACT 1,3-Dioxan-5-yl pyrimidine and purine nucleoside analogues were prepared following a new and versatile synthetic strategy. These analogues were synthesized via nucleophilic addition of the selected nucleobase to a 1,3-dioxane scaffold that presents an appropriate leaving group in position 5. In particular cis and trans isomers of purine/pyrimidine nucleosides and their halogenated homologues were obtained. NMR experiments, carried out on the cis isomers, led to assignment of an equatorial orientation to the 2-hydroxymethyl group and axial orientation to the nucleobase in position 5 of the 1,3-dioxane. The trans isomers showed a diequatorial orientation of these groups. These assignments were confirmed by X-ray crystallographic studies.
ChemInform, 2014
ABSTRACT Small amounts of the trans-products as well as five-membered ring acetals are often dete... more ABSTRACT Small amounts of the trans-products as well as five-membered ring acetals are often detected in the crude reaction mixtures.
Journal of Chromatography A, 2016
Almost all Iridium(III) complexes employed both as dopants in PhOLEDs and as pharmaceuticals and ... more Almost all Iridium(III) complexes employed both as dopants in PhOLEDs and as pharmaceuticals and fluorescence bioprobes are racemic mixtures. In this study the single enantiomers of the most stable diastereomeric form fac-trans-N-N, bis[2-(4,6-difluorophenyl)pyridinato-C(2),N](picolinato)iridium(III) (FIrpic) were separated and analysed. The data obtained showed that the complex can be separated into stable optically active Λ and Δ isomers employing cellulose based chiral stationary phase both in normal and polar phase mode. Their chirality was confirmed and their absolute configuration assigned employing several methods (DFT and TDDFT calculations, CD and VCD). The CPL spectroscopy of the isolated enantiomers of FIrpic was also recorded due to its possible value in the OLEDs field. The chromatographic method was applied for a semipreparative purpose demonstrating that polar organic solvent chromatography (POSC) could be used to avoid the low-solubility issues associated with these Iridium(III) complexes. Finally, the chemical and stereochemical stability of the single isomers was evaluated under thermal stress by liquid chromatography coupled to high-resolution mass spectrometry (LC-QTOF) on both chiral and achiral columns. No racemization and/or isomerization was observed; however, the dissociation of the ancillary ligand was demonstrated employing LC-QTOF.
Journal of Chromatography A, 2016
A "heart-cut" two-dimensional a... more A "heart-cut" two-dimensional achiral-chiral liquid chromatography triple-quadrupole mass spectrometry method (LC-LC-MS/MS) was developed and coupled to in vivo cerebral microdialysis to evaluate the brain response to the chiral compound (±)-7-chloro-5-(3-furanyl)-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide ((±)-1), a potent positive allosteric modulator (PAM) of AMPA receptor. The method was successfully employed to evaluate also its stereoselective metabolism and in vitro biological activity. In particular, the LC achiral method developed, employs a pentafluorinated silica based column (Discovery HS-F5) to separate dopamine, acetylcholine, serotonin, (±)-1 and its two hepatic metabolites. In the "heart-cut" two-dimension achiral-chiral configuration, (±)-1 and (±)-1-d4 eluted from the achiral column (1st dimension), were transferred to a polysaccharide-based chiral column (2nd dimension, Chiralcel OD-RH) by using an automatic six-port valve. Single enantiomers of (±)-1 were separated and detected using electrospray positive ionization mode and quantified in selected reaction monitoring mode. The method was validated and showed good performance in terms of linearity, accuracy and precision. The new method employed showed several possible applications in the evaluation of: (a) brain response to neuroactive compounds by measuring variations in the brain extracellular levels of selected neurotransmitters and other biomarkers; (b) blood brain barrier penetration of drug candidates by measuring the free concentration of the drug in selected brain areas; (c) the presence of drug metabolites in the brain extracellular fluid that could prove very useful during drug discovery; (d) a possible stereoselective metabolization or blood brain barrier stereoselective crossing of chiral drugs. Finally, compared to the methods reported in the literature, this technique avoids the necessity of euthanizing an animal at each time point to measure drug concentration in whole brain tissue and provides continuous monitoring of extracellular concentrations of single chiral drug enantiomers along with its metabolites in specific brain regions at each selected time point for a desired period by using a single animal.
ACS chemical neuroscience, Jan 18, 2015
5-Arylbenzothiadiazine type compounds acting as positive allosteric modulators of AMPA receptor (... more 5-Arylbenzothiadiazine type compounds acting as positive allosteric modulators of AMPA receptor (AMPA-PAMs) have received particular attention in the last decade for their nootropic activity and lack of the excitotoxic side effects of direct agonists. Recently, our research group has published the synthesis and biological activity of 7-chloro-5-(3-furanyl)-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide (1), one of the most active benzothiadiazine-derived AMPA-PAMs in vitro to date. However, 1 exists as two stereolabile enantiomers, which rapidly racemise in physiological conditions and only one isomer is responsible for the pharmacological activity. In the present work, experiments carried out with rat liver microsomes show that 1 is converted by hepatic cytochrome P450 to the corresponding unsaturated derivative 2 and to the corresponding pharmacologically inactive benzenesulfonamide 3. Surprisingly, patch-clamp experiments reveal that 2 displays an activity comparable ...
Tetrahedron Letters, 2012
A new efficient and versatile synthesis to obtain different substituted 5,6-dihydro-8H-[1,2,4]thi... more A new efficient and versatile synthesis to obtain different substituted 5,6-dihydro-8H-[1,2,4]thiadiazino[6,5,4-de]phenanthridine 4,4-dioxide and 5,6-dihydro-8H-[1,2,4]-thiadiazino[6,5,4-ij]thieno[2,3c]quinolone 4,4-dioxide was developed. The four cyclic systems are achieved by a three-step synthesis proceeding under mild conditions in high yields.
ChemInform, 2012
Efficient Synthesis of 5,6-Dihydro-8H-[1,2,4]thiadiazino[6,5,4-de]phenanthridine 4,4-Dioxide and ... more Efficient Synthesis of 5,6-Dihydro-8H-[1,2,4]thiadiazino[6,5,4-de]phenanthridine 4,4-Dioxide and 5,6-Dihydro-8H-[1,2,4]-thiadiazino[6,5,4-ij]thieno[2,3-c]quinoline 4,4-Dioxide. -The three-step synthesis of the title compounds is based on formation of key intermediates (III) and (VIII) from substrate (I) and boronic acids via Suzuki coupling and imine formation. -(BATTISTI, U. M.; CARROZZO, M. M.; CANNAZZA*, G.; BRAGHIROLI, D.; PARENTI, C.; BRASILI, L.; CITTI, C.; TROISI, L.; Tetrahedron Lett. 53 (2012) 9, 1122-1125, http://dx.doi.org/10.1016/j.tetlet.2011.12.091 ; Dip. Sci. Farm., Univ. Modena, I-41100 Modena, Italy; Eng.) -Mais 24-177
Tetrahedron Letters, 2012
ACS Medicinal Chemistry Letters, 2012
The potential therapeutic benefit of compounds able to activate AMPA receptors (AMPAr) has led to... more The potential therapeutic benefit of compounds able to activate AMPA receptors (AMPAr) has led to the search for new AMPAr positive modulators. On the basis of crystallographic data of the benzothiadiazines binding mode in the S1S2 GluA2 dimer interface, a set of 5-aryl-2,3dihydrobenzothiadiazine type compounds has been synthesized and tested. Electrophysiological results suggested that 5-heteroaryl substituents on the benzothiadiazine core like 3-furanyl and 3-thiophenyl dramatically enhance the activity as positive modulators of AMPAr with respect to IDRA21 and cyclothiazide. Mouse brain microdialysis studies have suggested that 7-chloro-5-(3-furyl)-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide crosses the blood−brain barrier after intraperitoneal injection. Biological results have been rationalized by a computational docking simulation that it has currently employed to design new AMPArpositive modulator candidates.
Journal of Chromatography A, 2016
Almost all Iridium(III) complexes employed both as dopants in PhOLEDs and as pharmaceuticals and ... more Almost all Iridium(III) complexes employed both as dopants in PhOLEDs and as pharmaceuticals and fluorescence bioprobes are racemic mixtures. In this study the single enantiomers of the most stable diastereomeric form fac-trans-N-N, bis[2-(4,6-difluorophenyl)pyridinato-C(2),N](picolinato)iridium(III) (FIrpic) were separated and analysed. The data obtained showed that the complex can be separated into stable optically active Λ and Δ isomers employing cellulose based chiral stationary phase both in normal and polar phase mode. Their chirality was confirmed and their absolute configuration assigned employing several methods (DFT and TDDFT calculations, CD and VCD). The CPL spectroscopy of the isolated enantiomers of FIrpic was also recorded due to its possible value in the OLEDs field. The chromatographic method was applied for a semipreparative purpose demonstrating that polar organic solvent chromatography (POSC) could be used to avoid the low-solubility issues associated with these Iridium(III) complexes. Finally, the chemical and stereochemical stability of the single isomers was evaluated under thermal stress by liquid chromatography coupled to high-resolution mass spectrometry (LC-QTOF) on both chiral and achiral columns. No racemization and/or isomerization was observed; however, the dissociation of the ancillary ligand was demonstrated employing LC-QTOF.
Journal of Chromatography A, 2016
A "heart-cut" two-dimensional achiral-chiral li... more A "heart-cut" two-dimensional achiral-chiral liquid chromatography triple-quadrupole mass spectrometry method (LC-LC-MS/MS) was developed and coupled to in vivo cerebral microdialysis to evaluate the brain response to the chiral compound (±)-7-chloro-5-(3-furanyl)-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide ((±)-1), a potent positive allosteric modulator (PAM) of AMPA receptor. The method was successfully employed to evaluate also its stereoselective metabolism and in vitro biological activity. In particular, the LC achiral method developed, employs a pentafluorinated silica based column (Discovery HS-F5) to separate dopamine, acetylcholine, serotonin, (±)-1 and its two hepatic metabolites. In the "heart-cut" two-dimension achiral-chiral configuration, (±)-1 and (±)-1-d4 eluted from the achiral column (1st dimension), were transferred to a polysaccharide-based chiral column (2nd dimension, Chiralcel OD-RH) by using an automatic six-port valve. Single enantiomers of (±)-1 were separated and detected using electrospray positive ionization mode and quantified in selected reaction monitoring mode. The method was validated and showed good performance in terms of linearity, accuracy and precision. The new method employed showed several possible applications in the evaluation of: (a) brain response to neuroactive compounds by measuring variations in the brain extracellular levels of selected neurotransmitters and other biomarkers; (b) blood brain barrier penetration of drug candidates by measuring the free concentration of the drug in selected brain areas; (c) the presence of drug metabolites in the brain extracellular fluid that could prove very useful during drug discovery; (d) a possible stereoselective metabolization or blood brain barrier stereoselective crossing of chiral drugs. Finally, compared to the methods reported in the literature, this technique avoids the necessity of euthanizing an animal at each time point to measure drug concentration in whole brain tissue and provides continuous monitoring of extracellular concentrations of single chiral drug enantiomers along with its metabolites in specific brain regions at each selected time point for a desired period by using a single animal.
European Journal of Medicinal Chemistry, 2016
Herein we report the synthesis and biological activity of new sigma receptor (σR) ligands obtaine... more Herein we report the synthesis and biological activity of new sigma receptor (σR) ligands obtained by combining different substituted five-membered heterocyclic rings with appropriate σR pharmacophoric amines. Radioligand binding assay, performed on guinea pig brain membranes, identified 25b (1-(1,4-dioxaspiro[4.5]decan-2-ylmethyl)-4-benzylpiperazine) as the most interesting compound of the series, displaying high affinity and selectivity for σ1R (pKiσ1 = 9.13; σ1/σ2 = 47). The ability of 25b to modulate the analgesic effect of the κ agonist (-)-U-50,488H and μ agonist morphine was evaluated in vivo by radiant heat tail-flick test. It exhibited anti-opioid effects on both κ and μ receptor-mediated analgesia, suggesting an agonistic behavior at σ1R. Docking studies were performed on the theoretical σ1R homology model. The present work represents a new starting point for the design of more potent and selective σ1R ligands.
Chirality, Sep 19, 2011
A stopped-flow bidimensional recycle HPLC (sf-BD-rHPLC) configuration has been used to investigat... more A stopped-flow bidimensional recycle HPLC (sf-BD-rHPLC) configuration has been used to investigate simultaneously the stereo and chemical stability of labile chiral compounds. The single enantiomers of a racemate can be separated on chiral column (first dimension) and each one can be trapped in the achiral column (second dimension) that works as reactor.By filling the achiral column with the appropriate aqueous buffers it is possible to evaluate the stability of the trapped enantiomer toward aqueous buffer itself. It was possible to recycle the reaction products formed in the chiral column (first dimension) where they are separated by a second six valve port. The reaction rate constants were calculated for the different processes occurred in the achiral column by means of corresponding peak areas. The method was applied to a pharmacological active compound: (±)7-chloro-5-ethyl-3-methyl-3,4-dihydro-2H-benzo[1,2,4]thiadiazine 1,1-dioxide ((±)-1) to evaluate enantiostability and hydrolysis in conditions similar to those of biological fluid. A classical batchwise kinetic method was used to calculate rate constants of hydrolysis and enantiomerization at the same temperature and in the same solvents used in sf-BD-rHPLC. The good agreement of the results obtained validate the novel procedure developed. Furthermore, the results generated off-line were used to determine the influence of solvents on the racemization of (±)-1.
ACS chemical neuroscience, Jan 18, 2015
5-Arylbenzothiadiazine type compounds acting as positive allosteric modulators of AMPA receptor (... more 5-Arylbenzothiadiazine type compounds acting as positive allosteric modulators of AMPA receptor (AMPA-PAMs) have received particular attention in the last decade for their nootropic activity and lack of the excitotoxic side effects of direct agonists. Recently, our research group has published the synthesis and biological activity of 7-chloro-5-(3-furanyl)-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide (1), one of the most active benzothiadiazine-derived AMPA-PAMs in vitro to date. However, 1 exists as two stereolabile enantiomers, which rapidly racemise in physiological conditions and only one isomer is responsible for the pharmacological activity. In the present work, experiments carried out with rat liver microsomes show that 1 is converted by hepatic cytochrome P450 to the corresponding unsaturated derivative 2 and to the corresponding pharmacologically inactive benzenesulfonamide 3. Surprisingly, patch-clamp experiments reveal that 2 displays an activity comparable ...
Tetrahedron Letters, 2012
A new efficient and versatile synthesis to obtain different substituted 5,6-dihydro-8H-[1,2,4]thi... more A new efficient and versatile synthesis to obtain different substituted 5,6-dihydro-8H-[1,2,4]thiadiazino[6,5,4-de]phenanthridine 4,4-dioxide and 5,6-dihydro-8H-[1,2,4]-thiadiazino[6,5,4-ij]thieno[2,3c]quinolone 4,4-dioxide was developed. The four cyclic systems are achieved by a three-step synthesis proceeding under mild conditions in high yields.
ChemInform, 2012
Efficient Synthesis of 5,6-Dihydro-8H-[1,2,4]thiadiazino[6,5,4-de]phenanthridine 4,4-Dioxide and ... more Efficient Synthesis of 5,6-Dihydro-8H-[1,2,4]thiadiazino[6,5,4-de]phenanthridine 4,4-Dioxide and 5,6-Dihydro-8H-[1,2,4]-thiadiazino[6,5,4-ij]thieno[2,3-c]quinoline 4,4-Dioxide. -The three-step synthesis of the title compounds is based on formation of key intermediates (III) and (VIII) from substrate (I) and boronic acids via Suzuki coupling and imine formation. -(BATTISTI, U. M.; CARROZZO, M. M.; CANNAZZA*, G.; BRAGHIROLI, D.; PARENTI, C.; BRASILI, L.; CITTI, C.; TROISI, L.; Tetrahedron Lett. 53 (2012) 9, 1122-1125, http://dx.doi.org/10.1016/j.tetlet.2011.12.091 ; Dip. Sci. Farm., Univ. Modena, I-41100 Modena, Italy; Eng.) -Mais 24-177
Journal of Chromatography A, 2014
Development of an in vitro Liquid Chromatography-Mass Spectrometry method to evaluate stereo and ... more Development of an in vitro Liquid Chromatography-Mass Spectrometry method to evaluate stereo and chemical stability of new drug candidates employing immobilized artificial membrane column, Journal of Chromatography A (2014), http://dx.
Tetrahedron Letters, 2010
A simple and efficient synthetic path for N-1 or N-2 alkyl-substituted 2-aminobenzenesulfonamides... more A simple and efficient synthetic path for N-1 or N-2 alkyl-substituted 2-aminobenzenesulfonamides was developed based on regioselective reduction with NaBH3CN in different solvents.
European Journal of Organic Chemistry, 2015
ABSTRACT (1,3-Dioxan-4-yl)-substituted nucleoside analogues, higher homologues of antiviral and a... more ABSTRACT (1,3-Dioxan-4-yl)-substituted nucleoside analogues, higher homologues of antiviral and anticancer 1,3-dioxolanes, were prepared from the key intermediate (4-acetoxy-1,3-dioxan-2-yl)methyl benzoate and silylated bases. Glycosylation, carried out under Vorbrüggen conditions in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) as a catalyst, afforded the desired compounds with high stereoselectivity and regioselectivity, with only the desired β-anomeric N-1 pyrimidine and N-9 purin nucleosides being obtained. 1H NMR experiments established that the β-anomers were diequatorial, and this assignment was confirmed by single-crystal X-ray diffraction. Despite their structural similarities with natural nucleosides, none of the synthesized nucleosides showed antiviral activity.
Synlett, 2015
ABSTRACT 1,3-Dioxan-5-yl pyrimidine and purine nucleoside analogues were prepared following a new... more ABSTRACT 1,3-Dioxan-5-yl pyrimidine and purine nucleoside analogues were prepared following a new and versatile synthetic strategy. These analogues were synthesized via nucleophilic addition of the selected nucleobase to a 1,3-dioxane scaffold that presents an appropriate leaving group in position 5. In particular cis and trans isomers of purine/pyrimidine nucleosides and their halogenated homologues were obtained. NMR experiments, carried out on the cis isomers, led to assignment of an equatorial orientation to the 2-hydroxymethyl group and axial orientation to the nucleobase in position 5 of the 1,3-dioxane. The trans isomers showed a diequatorial orientation of these groups. These assignments were confirmed by X-ray crystallographic studies.
ChemInform, 2014
ABSTRACT Small amounts of the trans-products as well as five-membered ring acetals are often dete... more ABSTRACT Small amounts of the trans-products as well as five-membered ring acetals are often detected in the crude reaction mixtures.