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Dive into the research topics where Silvia Gobbi is active.

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Featured researches published by Silvia Gobbi.


Journal of Medicinal Chemistry | 2008

Novel Aldosterone Synthase Inhibitors with Extended Carbocyclic Skeleton by a Combined Ligand-Based and Structure-Based Drug Design Approach

Simon Lucas; Ralf Heim; Matthias Negri; Iris Antes; Christina Ries; Katarzyna E. Schewe; Alessandra Bisi; Silvia Gobbi; Rolf W. Hartmann

Pharmacophore modeling of a series of aldosterone synthase (CYP11B2) inhibitors triggered the design of compounds 11 and 12 by extending a previously established naphthalene molecular scaffold (e.g., present in molecules 1 and 2) via introduction of a phenyl or benzyl residue in 3-position. These additional aromatic moieties have been hypothesized to fit into the newly identified hydrophobic pharmacophore feature HY3. Subsequent docking studies in our refined CYP11B2 protein model have been performed prior to synthesis to estimate the inhibitory properties of the proposed molecules. While phenyl-substituted compound 11 (IC50 > 500 nM) did not dock under the given pharmacophore constraint (i.e., the Fe(heme)-N(ligand) interaction), benzyl-substituted compound 12 (IC50 = 154 nM) was found to exploit a previously unexplored subpocket of the inhibitor binding site. By structural optimization based on the pharmacophore hypothesis, 25 novel compounds were synthesized, among them highly potent CYP11B2 inhibitors (e.g., 17, IC50 = 2.7 nM) with pronounced selectivity toward the most important steroidogenic and hepatic CYP enzymes.


Applied and Environmental Microbiology | 2004

Characterization and heterologous expression of the oxalyl coenzyme A decarboxylase gene from Bifidobacterium lactis.

Federica Federici; Beatrice Vitali; Roberto Gotti; Maria Rosalia Pasca; Silvia Gobbi; Ammon B. Peck; Patrizia Brigidi

ABSTRACT Oxalyl coenzyme A (CoA) decarboxylase (Oxc) is a key enzyme in the catabolism of the highly toxic compound oxalate, catalyzing the decarboxylation of oxalyl-CoA to formyl-CoA. The gene encoding a novel oxalyl-CoA decarboxylase from Bifidobacterium lactis DSM 10140 (oxc) was identified and characterized. This strain, isolated from yogurt, showed the highest oxalate-degrading activity in a preliminary screening with 12 strains belonging to Bifidobacterium, an anaerobic intestinal bacterial group largely used in probiotic products. The oxc gene was isolated by probing a B. lactis genomic library with a probe obtained by amplification of the oxalyl-CoA decarboxylase gene from Oxalobacter formigenes, an anaerobic bacterium of the human intestinal microflora. The oxc DNA sequence analysis revealed an open reading frame of 1,773 bp encoding a deduced 590-amino-acid protein with a molecular mass of about 63 kDa. Analysis of amino acid sequence showed a significant homology (47%) with oxalyl-CoA decarboxylase of O. formigenes and a typical thiamine pyrophosphate-binding site that has been reported for several decarboxylase enzymes. Primer extension experiments with oxc performed by using RNA isolated from B. lactis identified the transcriptional start site 28 bp upstream of the ATG start codon, immediately adjacent to a presumed promoter region. The protein overexpressed in Escherichia coli cross-reacted with an anti-O. formigenes oxalyl-CoA decarboxylase antibody. Enzymatic activity, when evaluated by capillary electrophoresis analysis, demonstrated that the consumption substrate oxalyl-CoA was regulated by a product inhibition of the enzyme. These findings suggest a potential role for Bifidobacterium in the intestinal degradation of oxalate.


Bioorganic & Medicinal Chemistry | 2008

Multidrug resistance reverting activity and antitumor profile of new phenothiazine derivatives

Alessandra Bisi; Maria Meli; Silvia Gobbi; Angela Rampa; Manlio Tolomeo; Luisa Dusonchet

A series of easily affordable phenothiazine derivatives bearing a rigid but-2-ynyl amino side chain were synthesized and tested to evaluate the MDR reverting activity and full antitumor profile. Some compounds endowed with remarkable MDR reverting effect were identified, and the most active one (6c) was shown to increase doxorubicin retention in multidrug resistant cells, suggesting a direct interaction with P-glycoprotein. Furthermore, a broad range of cellular activities were observed for different compounds. In particular, the ability of some derivatives to induce antiproliferative effects on resistant cell lines and to interfere with the G(1) phase of the cell cycle, a phase usually not affected by classical antitumor agents, was noted. Moreover, the most cytotoxic compounds of the series were able to induce apoptosis in resistant cell lines, via an atypical pathway of caspase cascade activation, and a synergistic effect in combination with doxorubicin was also found.


European Journal of Medicinal Chemistry | 2009

Design, synthesis, and evaluation of benzophenone derivatives as novel acetylcholinesterase inhibitors

Federica Belluti; Lorna Piazzi; Alessandra Bisi; Silvia Gobbi; Manuela Bartolini; Andrea Cavalli; Piero Valenti; Angela Rampa

Starting from a structure-based drug design, new acetylcholinesterase inhibitors were designed and synthesized as analogues of donepezil. The compounds were composed by an aromatic function and a tertiary amino moiety connected by a suitable spacer. In particular, the benzophenone nucleus and the N,N-benzylmethylamine function were selected. The easily accessible three-step synthesis of these compounds resulted to be significantly less difficult and expensive than that of donepezil. Several compounds possess anti-cholinesterase activity in the order of micro and sub-micromolar. Particularly, compounds 1 and 10 were the most potent inhibitors of the series.


Current Topics in Medicinal Chemistry | 2008

From Nonsteroidal Aromatase Inhibitors to Multifunctional Drug Candidates: Classic and Innovative Strategies for the Treatment of Breast Cancer

Silvia Gobbi; Andrea Cavalli; Alessandra Bisi; Maurizio Recanatini

Aromatase is the enzyme responsible for the conversion of androgens to estrogens and represents the main source of local estrogens in post-menopausal breast cancer tissue. Nonsteroidal aromatase inhibitors (NSAIs) are able to reduce growth-stimulatory effects of estrogens in hormone-dependent breast cancer, and third generation NSAIs are currently approved as first-line therapy for the treatment of postmenopausal women with metastatic advanced breast cancer. Nevertheless, some issues in this area still need to be addressed and research efforts are aimed both at identifying new molecules of therapeutic interest and at exploring different options for the modulation of this enzyme. In this review, an update of the latest developments in the field of NSAIs is presented, to provide a broad view on the recent progress in this area. Beside classical structure-activity relationships studies and development of natural product derivatives, rational approaches for both ligand- and structure-based design are described. Moreover, novel strategies for the development of multitarget-directed molecules are also presented. Finally, some possible future developments in this research area are briefly considered.


Journal of Medicinal Chemistry | 2006

Lead optimization providing a series of flavone derivatives as potent nonsteroidal inhibitors of the cytochrome P450 aromatase enzyme.

Silvia Gobbi; Andrea Cavalli; Angela Rampa; Federica Belluti; Lorna Piazzi; Anja Paluszcak; Rolf W. Hartmann; Maurizio Recanatini; Alessandra Bisi


Journal of Medicinal Chemistry | 2007

Imidazolylmethylbenzophenones as Highly Potent Aromatase Inhibitors

Silvia Gobbi; Andrea Cavalli; Matthias Negri; Katarzyna E. Schewe; Federica Belluti; Lorna Piazzi; Rolf W. Hartmann; Maurizio Recanatini; Alessandra Bisi


Journal of Medicinal Chemistry | 2007

Extensive SAR and Computational Studies of 3-{4-[(Benzylmethylamino)methyl]phenyl}-6,7-dimethoxy-2H-2-chromenone (AP2238) Derivatives

Lorna Piazzi; Andrea Cavalli; Federica Belluti; Alessandra Bisi; Silvia Gobbi; Stefano Rizzo; Manuela Bartolini; Vincenza Andrisano; and Maurizio Recanatini; Angela Rampa


Journal of Medicinal Chemistry | 2005

Enantioselective nonsteroidal aromatase inhibitors identified through a multidisciplinary medicinal chemistry approach.

Andrea Cavalli; Alessandra Bisi; Carlo Bertucci; Carlo Rosini; Anja Paluszcak; Silvia Gobbi; Egidio Giorgio; Angela Rampa; Federica Belluti; Lorna Piazzi; Piero Valenti; Rolf W. Hartmann; Maurizio Recanatini


Bioorganic & Medicinal Chemistry | 2005

1,4-dihydropyridine derivatives as calcium channel modulators: the role of 3-methoxy-flavone moiety

Roberta Budriesi; Alessandra Bisi; Pierfranco Ioan; Angela Rampa; Silvia Gobbi; Federica Belluti; Lorna Piazzi; Piero Valenti; Alberto Chiarini

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