Francesca Clerici | Università degli Studi di Milano - State University of Milan (Italy) (original) (raw)
Papers by Francesca Clerici
The Journal of Organic Chemistry, 2015
A new α,α-disubstituted constrained glutamine analogue has been designed to decorate gold nanopar... more A new α,α-disubstituted constrained glutamine analogue has been designed to decorate gold nanoparticles and to induce a 310-helix when inserted in peptides. Using an efficient "one-pot" asymmetric Schmidt reaction between 4-disubstituted-cyclohexanone and hydroxyalkylazides, 1H-azepine-2-oxo-5-amino-5-carboxylic acid was prepared. The main (R) isomer was inserted at the N-terminus in a very short peptide sequence (i.e., PhCO-(R)-Oxo-Azn-l-Ala-Aib-l-AlaNHMe) and a stable 310-helix conformation was obtained, as verified by both NMR experiments and molecular dynamics (MD) simulations. Finally, the presence of the hydroxyl chain at the nitrogen atom of the ring allowed for the preparation of covered chiral gold nanoparticles.
Journal of Molecular Structure: THEOCHEM, 2005
The mechanism for the nucleophilic reaction between methylthiolate and 4-bromo-3-methylamino-isot... more The mechanism for the nucleophilic reaction between methylthiolate and 4-bromo-3-methylamino-isothiazole 1,1-dioxide has been investigated on the basis of ab initio, MP2 and DFT calculations. Comparison of the computational results with the experimental findings led to the proposal of an unusual nucleophilic addition-elimination reaction mechanism proceeding through a 1,5-sigmatropic hydrogen shift. q
Tetrahedron: Asymmetry, 2009
Herein we report a mild and efficient method to synthesize chiral 3-aminosubstituted isothiazole ... more Herein we report a mild and efficient method to synthesize chiral 3-aminosubstituted isothiazole sulfoxides taking advantage of (+)- and (−)-((8,8-dichlorocamphoryl)sulfonyl)oxaziridine under microwave irradiation. The determination of the absolute configuration of the chiral sulfoxide was achieved by theoretical calculation of the CD spectra. The reason for the observed stereoselectivity was enlightened by means of analysis of our data using DFT calculations.
Tetrahedron, 2009
The asymmetric synthesis of new tetrahydropyrrolo [2, 3-b] indole 19 and tetrahydropyrano [2, 3-b... more The asymmetric synthesis of new tetrahydropyrrolo [2, 3-b] indole 19 and tetrahydropyrano [2, 3-b] indole 20 rings, substituted in position C-3a and C-4a with a hydroxy-and an amino functionalized chain, respectively, was performed starting from the racemic spiro [cyclohexane-1, 3′-indoline]-2′, 4-diones 7. The enantiopure spiro oxo-azepinoindolinone (+)-10, obtained from (±)-7 by the way of an asymmetric ring enlargement, and the amino acid (+)-14, obtained by the hydrolysis of 10, were prepared ...
Tetrahedron, 2003
Title investigation is presented with a view to SAR studies on the Trypanosoma brucei protein far... more Title investigation is presented with a view to SAR studies on the Trypanosoma brucei protein farnesyltransferase inhibitory activity of this class of compounds. -(CLERICI*, F.; CONTINI, A.; GELMI, M. L.; POCAR, D.; Tetrahedron 59 (2003) 47, 9399-9408; Ist. Chim. Org., Fac. Farm., Univ. Stud. Milano, I-20133 Milano, Italy; Eng.) -Nuesgen 10-128
Neuroscience Letters, 2007
Folic acid is believed to play a role in protection from oxidant stress. Low levels of folic acid... more Folic acid is believed to play a role in protection from oxidant stress. Low levels of folic acid had been found in serum from patients with Alzheimer disease (AD). Folate concentration was evaluated in sera from 136 patients with cortical dementia [AD, n = 108; frontotemporal dementia (FTD), n = 28], 57 patients with subcortical dementia [Lewy body disease (LBD), n = 9; corticobasal degeneration (CBD), n = 5; progressive supranuclear palsy (PSP), n = 6; Parkinson disease with dementia (PD-Dem), n = 37], and 76 nondemented, healthy age-matched people. Serum folic acid levels were decreased in patients with AD and FTD as compared with either controls or patients with subcortical dementia (3.60 ± 2.22 and 5.37 ± 2.92 g/L versus 6.87 ± 3.50 g/L, respectively; P < 0.01). A tendency towards decreased folate concentration was found in LBD and CBD, but not to a significant extent. The highest proportion of folate-deficient patients was found in CBD, FTD and AD (respectively, 60, 48.2 and 46.3% versus 7.9% in controls; P < 0.001). Folate deficiency characterizes FTD as well as AD. These differences observed among different clinical dementing syndromes may be related to neocortical damage.
MedChemComm, 2013
Through a computational approach, five new compounds with potent and selective Rac inhibitory act... more Through a computational approach, five new compounds with potent and selective Rac inhibitory activity were identified. In particular, compound 4 was shown to selectively inhibit Rac activity in a concentration-dependent manner by 10 affecting the GEF-dependent GDP-GTP exchange. This compound was more potent than the original inhibitors previously identified.
Letters in Organic Chemistry, 2008
The present paper describes a mild and efficient method to synthesize 3-aminosubstituted isothiaz... more The present paper describes a mild and efficient method to synthesize 3-aminosubstituted isothiazole sulfoxides taking advantage of arylsulfonyloxaziridines. The reactivity of the resulting isothiazole sulfoxides toward sulfur nucleophiles has been studied and resulted in the formation of 5-sulfanylsubstituted isothiazoles in a fully diastereoselective way. From 3-benzylamino-5-chloro isothiazole S-oxide an addition-elimination reaction took place affording smoothly the corresponding unsaturated 5-sulfanyl derivatives.
Journal of Molecular Graphics and Modelling, 2013
We describe the application of molecular dynamics followed by principal component analysis to stu... more We describe the application of molecular dynamics followed by principal component analysis to study the inter-domain movements of the ligand binding domain (LBD) of mGluR5 in response to the binding of selected agonists or antagonists. Our results suggest that the method is an attractive alternative to current approaches to predict the agonist-induced or antagonist-blocked LBD responses. The ratio between the eigenvalues of the first and second eigenvectors (R1,2) is also proposed as a numerical descriptor for discriminating the ligand behavior as a mGluR5 agonist or antagonist.
Journal of Medicinal Chemistry, 2009
Rac1 protein is implicated in several events of atherosclerotic plaque development and represents... more Rac1 protein is implicated in several events of atherosclerotic plaque development and represents a new potential pharmacological target for cardiovascular diseases. In this paper we describe a pharmacophore virtual screening followed by molecular docking calculations leading to the identification of five new Rac1 inhibitors. These compounds were shown to be more effective than the reference compound NSC23766 in reducing the intracellular levels of Rac1-GTP, thus supporting this approach for the development of new Rac1 inhibitors.
Journal of Medicinal Chemistry, 2014
The use of the 2-amino-3-(phenylsulfanyl)norbornane-2-carboxylate scaffold has been exploited for... more The use of the 2-amino-3-(phenylsulfanyl)norbornane-2-carboxylate scaffold has been exploited for the de novo design of potent Rac1 inhibitors acting as modulators of the protein-protein interaction between Rac1 and Tiam1. A series of compounds differing in regio- and stereochemistry has been prepared by way of a multistep synthesis based on cycloaddition reactions and Pd chemistry. Pharmacological analyses showed that all the prepared compounds were active and selective for Rac1, and the most effective compound 13 was capable of inhibiting smooth muscle cell migration. The synthesis of this derivative was successfully scaled up to 1 g.
Helvetica Chimica Acta, 2009
The racemic N-benzylisothiazol-3-amine 1-oxide (2) was demonstrated to be an efficient partner in... more The racemic N-benzylisothiazol-3-amine 1-oxide (2) was demonstrated to be an efficient partner in Diels -Alder reactions (Schemes 2 -4) and a good dipolarophile in 1,3-dipolar cycloaddition reactions with nitrile oxides (Scheme 5). Polycyclic isothiazole S-oxides with different substitution patterns were obtained from 2 in good yield and in a fully regioselective way. Improved diastereoselection was observed performing the Diels -Alder or 1,3-dipolar cycloaddition reactions in H 2 O.
Current Organic Chemistry, 2011
Abstract: A new series of organocatalysts able to catalyse Diels-Alder cycloaddition reactions of... more Abstract: A new series of organocatalysts able to catalyse Diels-Alder cycloaddition reactions of α, β-unsaturated aldehydes was studied from both synthetic and theoretical perspectives. The importance of the imidazolidinone scaffold and the influence of the functional groups upon the formation of the reactive species was evaluated. Moreover taking into account that all these new organocatalysts gave the exo-cycloadducts as the major isomers with high selectivity a theoretical study was realized to try and define the essential ...
Chemistry - A European Journal, 2012
A very efficient synthesis of orthogonally protected 1H-azepine-4-amino-4-carboxylic acid, abbrev... more A very efficient synthesis of orthogonally protected 1H-azepine-4-amino-4-carboxylic acid, abbreviated as Azn, a conformationally restricted analogue of ornithine, was realized. It was obtained on a gram scale in good overall yield in five steps, three of which did not require isolation of the intermediates, starting from the readily available 1-amino-4-oxo-cyclohexane-4-carboxylic acid. Both enantiomers were used for the preparation of pentapeptide models containing Ala, Aib, and Azn. Conformational studies using both spectroscopic techniques (NMR, CD) and molecular dynamics on model 5-mer peptides showed that the (R)-Azn isomer possesses a marked helicogenic effect.
Bioorganic & Medicinal Chemistry Letters, 2002
A series of isothiazole dioxides was synthesized and evaluated as inhibitors of protein farnesylt... more A series of isothiazole dioxides was synthesized and evaluated as inhibitors of protein farnesyltransferase from the parasite that causes African sleeping sickness (Trypanosoma brucei). The most potent compound in the series inhibited the parasite enzyme with an IC 50 of 2 mM and blocked the growth of the bloodstream parasite in vitro with an ED 50 of 10 mM. The same compound inhibited rat protein farnesyltransferase and protein geranylgeranyltransferase type I only at much higher concentration. #
Asymmetric synthesis and absolute configuration of 3-aminosubstituted isothiazole S-oxides / F. C... more Asymmetric synthesis and absolute configuration of 3-aminosubstituted isothiazole S-oxides / F. Clerici, A. Casoni, G. Celentano, A. Contini, S. Pellegrino, G. Mazzeo, C. Rosini. ((Intervento presentato al 12. convegno International Conference on Circular Dichroism ISBC, Interdisciplinary Symposium on Biological Chirality tenutosi a Brescia nel 2009. ... There are no files associated with this item. ... Items in AIR are protected by copyright, with all rights reserved, unless otherwise indicated. ... ICT Support, development & maintenance are provided by the AePIC team ...
European journal of medicinal chemistry, May 31, 2006
5-Sulfanyl-3-alkylaminoisothiazole dioxide derivatives have been identified as a new class of pot... more 5-Sulfanyl-3-alkylaminoisothiazole dioxide derivatives have been identified as a new class of potent inhibitors of rat aortic myocite proliferation. They were prepared by applying a simple methodology able to introduce a heteroatom on C-5 of the 3-alkylaminoisothiazole dioxide system. 3-Aminosubstituted-5-chloroisothiazole dioxides react smoothly not only with S-nucleophiles but also with N-and O-nucleophiles affording the corresponding 5-heterosubstituted isothiazole dioxides through an addition–elimination reaction. The ...
The Journal of Organic Chemistry, 2015
A new α,α-disubstituted constrained glutamine analogue has been designed to decorate gold nanopar... more A new α,α-disubstituted constrained glutamine analogue has been designed to decorate gold nanoparticles and to induce a 310-helix when inserted in peptides. Using an efficient &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;one-pot&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; asymmetric Schmidt reaction between 4-disubstituted-cyclohexanone and hydroxyalkylazides, 1H-azepine-2-oxo-5-amino-5-carboxylic acid was prepared. The main (R) isomer was inserted at the N-terminus in a very short peptide sequence (i.e., PhCO-(R)-Oxo-Azn-l-Ala-Aib-l-AlaNHMe) and a stable 310-helix conformation was obtained, as verified by both NMR experiments and molecular dynamics (MD) simulations. Finally, the presence of the hydroxyl chain at the nitrogen atom of the ring allowed for the preparation of covered chiral gold nanoparticles.
Journal of Molecular Structure: THEOCHEM, 2005
The mechanism for the nucleophilic reaction between methylthiolate and 4-bromo-3-methylamino-isot... more The mechanism for the nucleophilic reaction between methylthiolate and 4-bromo-3-methylamino-isothiazole 1,1-dioxide has been investigated on the basis of ab initio, MP2 and DFT calculations. Comparison of the computational results with the experimental findings led to the proposal of an unusual nucleophilic addition-elimination reaction mechanism proceeding through a 1,5-sigmatropic hydrogen shift. q
Tetrahedron: Asymmetry, 2009
Herein we report a mild and efficient method to synthesize chiral 3-aminosubstituted isothiazole ... more Herein we report a mild and efficient method to synthesize chiral 3-aminosubstituted isothiazole sulfoxides taking advantage of (+)- and (−)-((8,8-dichlorocamphoryl)sulfonyl)oxaziridine under microwave irradiation. The determination of the absolute configuration of the chiral sulfoxide was achieved by theoretical calculation of the CD spectra. The reason for the observed stereoselectivity was enlightened by means of analysis of our data using DFT calculations.
Tetrahedron, 2009
The asymmetric synthesis of new tetrahydropyrrolo [2, 3-b] indole 19 and tetrahydropyrano [2, 3-b... more The asymmetric synthesis of new tetrahydropyrrolo [2, 3-b] indole 19 and tetrahydropyrano [2, 3-b] indole 20 rings, substituted in position C-3a and C-4a with a hydroxy-and an amino functionalized chain, respectively, was performed starting from the racemic spiro [cyclohexane-1, 3′-indoline]-2′, 4-diones 7. The enantiopure spiro oxo-azepinoindolinone (+)-10, obtained from (±)-7 by the way of an asymmetric ring enlargement, and the amino acid (+)-14, obtained by the hydrolysis of 10, were prepared ...
Tetrahedron, 2003
Title investigation is presented with a view to SAR studies on the Trypanosoma brucei protein far... more Title investigation is presented with a view to SAR studies on the Trypanosoma brucei protein farnesyltransferase inhibitory activity of this class of compounds. -(CLERICI*, F.; CONTINI, A.; GELMI, M. L.; POCAR, D.; Tetrahedron 59 (2003) 47, 9399-9408; Ist. Chim. Org., Fac. Farm., Univ. Stud. Milano, I-20133 Milano, Italy; Eng.) -Nuesgen 10-128
Neuroscience Letters, 2007
Folic acid is believed to play a role in protection from oxidant stress. Low levels of folic acid... more Folic acid is believed to play a role in protection from oxidant stress. Low levels of folic acid had been found in serum from patients with Alzheimer disease (AD). Folate concentration was evaluated in sera from 136 patients with cortical dementia [AD, n = 108; frontotemporal dementia (FTD), n = 28], 57 patients with subcortical dementia [Lewy body disease (LBD), n = 9; corticobasal degeneration (CBD), n = 5; progressive supranuclear palsy (PSP), n = 6; Parkinson disease with dementia (PD-Dem), n = 37], and 76 nondemented, healthy age-matched people. Serum folic acid levels were decreased in patients with AD and FTD as compared with either controls or patients with subcortical dementia (3.60 ± 2.22 and 5.37 ± 2.92 g/L versus 6.87 ± 3.50 g/L, respectively; P < 0.01). A tendency towards decreased folate concentration was found in LBD and CBD, but not to a significant extent. The highest proportion of folate-deficient patients was found in CBD, FTD and AD (respectively, 60, 48.2 and 46.3% versus 7.9% in controls; P < 0.001). Folate deficiency characterizes FTD as well as AD. These differences observed among different clinical dementing syndromes may be related to neocortical damage.
MedChemComm, 2013
Through a computational approach, five new compounds with potent and selective Rac inhibitory act... more Through a computational approach, five new compounds with potent and selective Rac inhibitory activity were identified. In particular, compound 4 was shown to selectively inhibit Rac activity in a concentration-dependent manner by 10 affecting the GEF-dependent GDP-GTP exchange. This compound was more potent than the original inhibitors previously identified.
Letters in Organic Chemistry, 2008
The present paper describes a mild and efficient method to synthesize 3-aminosubstituted isothiaz... more The present paper describes a mild and efficient method to synthesize 3-aminosubstituted isothiazole sulfoxides taking advantage of arylsulfonyloxaziridines. The reactivity of the resulting isothiazole sulfoxides toward sulfur nucleophiles has been studied and resulted in the formation of 5-sulfanylsubstituted isothiazoles in a fully diastereoselective way. From 3-benzylamino-5-chloro isothiazole S-oxide an addition-elimination reaction took place affording smoothly the corresponding unsaturated 5-sulfanyl derivatives.
Journal of Molecular Graphics and Modelling, 2013
We describe the application of molecular dynamics followed by principal component analysis to stu... more We describe the application of molecular dynamics followed by principal component analysis to study the inter-domain movements of the ligand binding domain (LBD) of mGluR5 in response to the binding of selected agonists or antagonists. Our results suggest that the method is an attractive alternative to current approaches to predict the agonist-induced or antagonist-blocked LBD responses. The ratio between the eigenvalues of the first and second eigenvectors (R1,2) is also proposed as a numerical descriptor for discriminating the ligand behavior as a mGluR5 agonist or antagonist.
Journal of Medicinal Chemistry, 2009
Rac1 protein is implicated in several events of atherosclerotic plaque development and represents... more Rac1 protein is implicated in several events of atherosclerotic plaque development and represents a new potential pharmacological target for cardiovascular diseases. In this paper we describe a pharmacophore virtual screening followed by molecular docking calculations leading to the identification of five new Rac1 inhibitors. These compounds were shown to be more effective than the reference compound NSC23766 in reducing the intracellular levels of Rac1-GTP, thus supporting this approach for the development of new Rac1 inhibitors.
Journal of Medicinal Chemistry, 2014
The use of the 2-amino-3-(phenylsulfanyl)norbornane-2-carboxylate scaffold has been exploited for... more The use of the 2-amino-3-(phenylsulfanyl)norbornane-2-carboxylate scaffold has been exploited for the de novo design of potent Rac1 inhibitors acting as modulators of the protein-protein interaction between Rac1 and Tiam1. A series of compounds differing in regio- and stereochemistry has been prepared by way of a multistep synthesis based on cycloaddition reactions and Pd chemistry. Pharmacological analyses showed that all the prepared compounds were active and selective for Rac1, and the most effective compound 13 was capable of inhibiting smooth muscle cell migration. The synthesis of this derivative was successfully scaled up to 1 g.
Helvetica Chimica Acta, 2009
The racemic N-benzylisothiazol-3-amine 1-oxide (2) was demonstrated to be an efficient partner in... more The racemic N-benzylisothiazol-3-amine 1-oxide (2) was demonstrated to be an efficient partner in Diels -Alder reactions (Schemes 2 -4) and a good dipolarophile in 1,3-dipolar cycloaddition reactions with nitrile oxides (Scheme 5). Polycyclic isothiazole S-oxides with different substitution patterns were obtained from 2 in good yield and in a fully regioselective way. Improved diastereoselection was observed performing the Diels -Alder or 1,3-dipolar cycloaddition reactions in H 2 O.
Current Organic Chemistry, 2011
Abstract: A new series of organocatalysts able to catalyse Diels-Alder cycloaddition reactions of... more Abstract: A new series of organocatalysts able to catalyse Diels-Alder cycloaddition reactions of α, β-unsaturated aldehydes was studied from both synthetic and theoretical perspectives. The importance of the imidazolidinone scaffold and the influence of the functional groups upon the formation of the reactive species was evaluated. Moreover taking into account that all these new organocatalysts gave the exo-cycloadducts as the major isomers with high selectivity a theoretical study was realized to try and define the essential ...
Chemistry - A European Journal, 2012
A very efficient synthesis of orthogonally protected 1H-azepine-4-amino-4-carboxylic acid, abbrev... more A very efficient synthesis of orthogonally protected 1H-azepine-4-amino-4-carboxylic acid, abbreviated as Azn, a conformationally restricted analogue of ornithine, was realized. It was obtained on a gram scale in good overall yield in five steps, three of which did not require isolation of the intermediates, starting from the readily available 1-amino-4-oxo-cyclohexane-4-carboxylic acid. Both enantiomers were used for the preparation of pentapeptide models containing Ala, Aib, and Azn. Conformational studies using both spectroscopic techniques (NMR, CD) and molecular dynamics on model 5-mer peptides showed that the (R)-Azn isomer possesses a marked helicogenic effect.
Bioorganic & Medicinal Chemistry Letters, 2002
A series of isothiazole dioxides was synthesized and evaluated as inhibitors of protein farnesylt... more A series of isothiazole dioxides was synthesized and evaluated as inhibitors of protein farnesyltransferase from the parasite that causes African sleeping sickness (Trypanosoma brucei). The most potent compound in the series inhibited the parasite enzyme with an IC 50 of 2 mM and blocked the growth of the bloodstream parasite in vitro with an ED 50 of 10 mM. The same compound inhibited rat protein farnesyltransferase and protein geranylgeranyltransferase type I only at much higher concentration. #
Asymmetric synthesis and absolute configuration of 3-aminosubstituted isothiazole S-oxides / F. C... more Asymmetric synthesis and absolute configuration of 3-aminosubstituted isothiazole S-oxides / F. Clerici, A. Casoni, G. Celentano, A. Contini, S. Pellegrino, G. Mazzeo, C. Rosini. ((Intervento presentato al 12. convegno International Conference on Circular Dichroism ISBC, Interdisciplinary Symposium on Biological Chirality tenutosi a Brescia nel 2009. ... There are no files associated with this item. ... Items in AIR are protected by copyright, with all rights reserved, unless otherwise indicated. ... ICT Support, development & maintenance are provided by the AePIC team ...
European journal of medicinal chemistry, May 31, 2006
5-Sulfanyl-3-alkylaminoisothiazole dioxide derivatives have been identified as a new class of pot... more 5-Sulfanyl-3-alkylaminoisothiazole dioxide derivatives have been identified as a new class of potent inhibitors of rat aortic myocite proliferation. They were prepared by applying a simple methodology able to introduce a heteroatom on C-5 of the 3-alkylaminoisothiazole dioxide system. 3-Aminosubstituted-5-chloroisothiazole dioxides react smoothly not only with S-nucleophiles but also with N-and O-nucleophiles affording the corresponding 5-heterosubstituted isothiazole dioxides through an addition–elimination reaction. The ...