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325 results on '"Barlocco D"'

1. Ureido-Pyridazinone Derivatives: Insights into the Structural and Conformational Properties for STAT3 Inhibition

Author

Meneghetti, F, Villa, S, Masciocchi, D, Barlocco, D, Toma, L, Han, D, Kwon, B, Ogo, N, Asai, A, Legnani, L, Gelain, A, Meneghetti F., Villa S., Masciocchi D., Barlocco D., Toma L., Han D. -C., Kwon B. -M., Ogo N., Asai A., Legnani L., Gelain A., Meneghetti, F, Villa, S, Masciocchi, D, Barlocco, D, Toma, L, Han, D, Kwon, B, Ogo, N, Asai, A, Legnani, L, Gelain, A, Meneghetti F., Villa S., Masciocchi D., Barlocco D., Toma L., Han D. -C., Kwon B. -M., Ogo N., Asai A., Legnani L., and Gelain A.

Abstract

Three new ureido-pyridazinone derivatives, which are structurally related to the known STAT3 inhibitor AVS-0288, were designed by taking into account the structure-activity relationships determined for several ureido-oxadiazole derivatives previously studied by our group. Their synthesis was first attempted through suitable 5-aminopyridazinone intermediates (6a and 6b), which molecular structures were confirmed by means of X-ray diffraction data on 6a. Amine functionalization was unsuccessful, therefore, an alternative method was devised. Dual-luciferase and AlphaScreen-based assays were used to test their activity. The obtained data were rationalized on the basis of a modeling study, which focused our attention on the geometrical preferences of the ureido moiety. Computational results seem to indicate that both the 1,2,5-oxadiazole ring and the extended ZZ arrangement are essential and probably act in a synergistic way to confer significant activity against STAT3.

Published
2015

2. Synthesis structure-activity relationships and stereochemical investigations of new tricyclic pyridazinone derivatives as potential STAT3 inhibitors

Author

Masciocchi, D, Gelain, A, Porta, F, Meneghetti, F, Pedretti, A, Celentano, C, Barlocco, D, Legnani, L, Toma, L, Kwon, B, Asai, A, Villa, S, Masciocchi D., Gelain A., Porta F., Meneghetti F., Pedretti A, Celentano C., Barlocco D., LEGNANI, LAURA, TOMA, LUCIO, Kwon B.M., Asai A., Villa S., Masciocchi, D, Gelain, A, Porta, F, Meneghetti, F, Pedretti, A, Celentano, C, Barlocco, D, Legnani, L, Toma, L, Kwon, B, Asai, A, Villa, S, Masciocchi D., Gelain A., Porta F., Meneghetti F., Pedretti A, Celentano C., Barlocco D., LEGNANI, LAURA, TOMA, LUCIO, Kwon B.M., Asai A., and Villa S.

Abstract

Through a cell-based biological screening, the benzocinnolinone derivative (±)-2c was identified as a promising STAT3 inhibitor. Since SAR studies on a series of compounds structurally related to (±)-2c (1c, 2a-p, 3c, 4c, 6) showed that the latter had the most significant inhibitory activity, we investigated in depth its essential structural features. In particular, enantiomeric separation was performed, and the absolute configuration of the stereoisomers was assigned by theoretical and crystallographic studies. The biological evaluation highlighted that (S)-(-)-2c is twice as potent as (R)-(+)-2c.

Published
2013

9. Exploring scaffolds to discover new STAT3 inhibitors, as novel anticancer agents

Author

Villa, S, Masciocchi, D, Gelain, A, Dell'Orto, S, Meneghetti, F, Pedretti, A, Barlocco, D, Legnani, L, Yoma, L, Kwon, B, Nakano, S, Asai, A, S. Villa, D. Masciocchi, A. Gelain, S. Dell'Orto, F. Meneghetti, A. Pedretti, D. Barlocco, L. Legnani, L. Yoma, B_M. Kwon, S. Nakano, A. Asai, Villa, S, Masciocchi, D, Gelain, A, Dell'Orto, S, Meneghetti, F, Pedretti, A, Barlocco, D, Legnani, L, Yoma, L, Kwon, B, Nakano, S, Asai, A, S. Villa, D. Masciocchi, A. Gelain, S. Dell'Orto, F. Meneghetti, A. Pedretti, D. Barlocco, L. Legnani, L. Yoma, B_M. Kwon, S. Nakano, and A. Asai

Published
2012

10. Synthesis, modeling, and crystallographic study of 3,4-disubstituted-1,2,5-oxadiazoles and evaluation of their ability to decrease STAT3 activity

Author

Shin Dae, S, Masciocchi, D, Gelain, A, Villa, S, Barlocco, D, Meneghetti, F, Pedretti, A, Han Young, M, Han Dong, C, Kwon Byoung, M, Legnani, L, Toma, L, Shin Dae Seop, Masciocchi Daniela, Gelain Arianna, Villa Stefania, Barlocco Daniela, Meneghetti Fiorella, Pedretti Alessandro, Han Young Min, Han Dong Cho, Kwon Byoung Mog, LEGNANI, LAURA, TOMA, LUCIO, Shin Dae, S, Masciocchi, D, Gelain, A, Villa, S, Barlocco, D, Meneghetti, F, Pedretti, A, Han Young, M, Han Dong, C, Kwon Byoung, M, Legnani, L, Toma, L, Shin Dae Seop, Masciocchi Daniela, Gelain Arianna, Villa Stefania, Barlocco Daniela, Meneghetti Fiorella, Pedretti Alessandro, Han Young Min, Han Dong Cho, Kwon Byoung Mog, LEGNANI, LAURA, and TOMA, LUCIO

Abstract

STAT3 (Signal Transducer and Activator of Transcription 3) is a transcription factor constitutively activated by aberrant upstream tyrosine kinase activities in a broad spectrum of human solid and blood tumors, thus suggesting that its inhibition could represent an interesting molecular target for cancer therapy. With the aim to disclose novel scaffolds for compounds active on STAT3 the potential of the 1,2,5-oxadiazole ring was explored and several new compounds substituted at positions 3 and 4 of the heterocycle were synthesized. When tested in a dual-luciferase assay, using HCT-116 cells, some compounds showed a significant inhibition value towards STAT3. So, to give support to the biological results, modeling and crystallographic studies of representative terms of the new series were performed.

Published
2010

11. Biphenyl versus Phenylpyridazine Derivatives: The Role of the Heterocycle in a Series of Acyl-CoA:Cholesterol Acyl Transferase Inhibitors

Author

Gelain, A, Barlocco, D, Kwon Byoung, M, Jeong Tae, S, Im Kyung, R, Legnani, L, Toma, L, Gelain Arianna, Barlocco Daniela, Kwon Byoung Mog, Jeong Tae Sook, Im Kyung Ran, LEGNANI, LAURA, TOMA, LUCIO, Gelain, A, Barlocco, D, Kwon Byoung, M, Jeong Tae, S, Im Kyung, R, Legnani, L, Toma, L, Gelain Arianna, Barlocco Daniela, Kwon Byoung Mog, Jeong Tae Sook, Im Kyung Ran, LEGNANI, LAURA, and TOMA, LUCIO

Abstract

A series of alkylamido- (1) and alkylaminobiphenyl (2) derivatives were synthesized as possible bioisosters of the reported ACAT inhibitors phenylpyridazine analogues (I). Both 1 and 2 were tested on the human ACAT-1 and ACAT-2 isoforms. The amino derivatives 2 were found to be inactive, contrary to the related pyridazine derivatives. By contrast, the ortho-substituted amides la and Id showed an interesting activity. These results support the essential role of the pyridazine nucleus. Modeling studies were also performed.

Published
2008

12. Structure-based design of an inhibitor modeled at the substrate active site of aldose reductase

Author

Rastelli, Giulio, Vianello, P., Barlocco, D., Costantino, Luca, Cignarella, G., DEL CORSO, A., and Mura, U.

Subjects
chemistry.chemical_classification, Aldose reductase, aldose reductase, molecular dynamics, docking, structure-based ligand design, biology, Molecular model, Stereochemistry, Carboxylic acid, Organic Chemistry, Clinical Biochemistry, Pharmaceutical Science, Active site, Biochemistry, Molecular mechanics, chemistry, Enzyme inhibitor, Docking (molecular), Drug Discovery, biology.protein, Molecular Medicine, Molecular Biology, Aldehyde Reductase
Abstract

This study presents the first successful example of structure-based drug design on aldose reductase in the extant literature. Starting from the structure of the modeled complex of aldose reductase with a pyridazinone acetic acid inhibitor that we previously disclosed, using the tools of molecular modeling for structure manipulation and molecular mechanics for energy minimization, we were able to design and synthesize a new analog that showed remarkably improved activity. We hope that a proper account of the most important enzyme-inhibitor interactions revealed by this study will allow, in the future, the design of new lead compounds having structures unrelated to carboxylic acids.

Published
1997

14. Thienocycloheptapyridazines as new muscarinic agents

Author

Barlocco, D., Cignarella, G., Francesca Fanelli, Vitalis, B., Matyus, P., and Benedetti, P. G.

Subjects
Male, computational modeling, muscarinic receptors, Muscarinic Antagonists, Muscarinic Agonists, Receptors, Muscarinic, Drug design, GPCRs, Rats, Pyridazines, Rats, Sprague-Dawley, Structure-Activity Relationship, Animals, Humans
Abstract

A series of thienocycloheptapyridazines (3aa-dd), structurally related to Minaprine, was synthesized and compounds tested for their affinity towards muscarinic receptors. All of them showed Ki values in the micromolar range towards both the antagonist 3H-QNB and the agonist 3H-OXO-M, thus indicating that they act as antagonists at the muscarinic receptors. Moreover a theoretical study was performed on their interaction behaviour with a three dimensional (3-D) model of the human m1 muscarinic receptor.

Published
1997

15. 3-Heptylamino-5-phenylpyridazine derivatives as analogues of acyl-CoA: cholesterol acyltransferase inhibitors containing the N-heptyl-N’-arylureidic moiety

Author

Gelain, A, Barlocco, D, KWON Byong, M, JEONG Tae, S, IM Kyung, R, Legnani, L, Toma, L, GELAIN Arianna, BARLOCCO Daniela, KWON Byong Mog, JEONG Tae Sook, IM Kyung Ran, LEGNANI, LAURA, TOMA, LUCIO, Gelain, A, Barlocco, D, KWON Byong, M, JEONG Tae, S, IM Kyung, R, Legnani, L, Toma, L, GELAIN Arianna, BARLOCCO Daniela, KWON Byong Mog, JEONG Tae Sook, IM Kyung Ran, LEGNANI, LAURA, and TOMA, LUCIO

Abstract

A series of novel Acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors 8a-f was synthesized; the substances were characterized by the presence of a 2,5-dimethylpyrazin-3-yl moiety at one end and a 3-heptylamino-5- phenylpyridazine system at the other one, linked through linear alkyl spacers of different length. The new derivatives were designed based on the hypothesis that the 3-amino-5-phenylpyridazine moiety could mimic the aryl substituted urea, which was present in a number of ACAT inhibitors previously described. The choice of the 2,5-dimethylpyrazin-3-yl substituent was supported by a preliminary investigation, which indicated that this moiety is the most powerful in conferring ACAT inhibitory properties to the new series. The pharmacological results proved the idea to be sound. Finally, compounds 9a-c, lacking the phenylpyridazine moiety were prepared and tested to further strengthen our hypothesis.

Published
2006

16. Ureidopyridazine derivatives as acyl-CoA:cholesterol acyltransferase inhibitors

Author

Gelain, A, Bettinelli, I, Barlocco, D, KWON Byoung, M, JEONG Tae, S, IM Kyung, R, Legnani, L, Toma, L, GELAIN Arianna, BETTINELLI Ilaria, BARLOCCO Daniela, KWON Byoung Mog, JEONG Tae Sook, IM Kyung Ran, LEGNANI, LAURA, TOMA, LUCIO, Gelain, A, Bettinelli, I, Barlocco, D, KWON Byoung, M, JEONG Tae, S, IM Kyung, R, Legnani, L, Toma, L, GELAIN Arianna, BETTINELLI Ilaria, BARLOCCO Daniela, KWON Byoung Mog, JEONG Tae Sook, IM Kyung Ran, LEGNANI, LAURA, and TOMA, LUCIO

Abstract

A series of N-(2,4-difluorophenyl)-N′-heptyl-N′-{4- [(substituted)-pyridazin-3-yl)thio]pentyl}urea derivatives having a phenyl ring at positions 5 and/or at position 6 of the heterocycle, as well as the corresponding sulfones, were synthesized. Their inhibitory activity against acyl-CoA:cholesterol acyltransferase (ACAT) was tested on the enzyme prepared from rat liver microsomes. Theoretical studies were performed to correlate their activity to their structural features.

Published
2006

17. 2-(Substituted)amino-2,8-diazaspiro[4,5]decan-1,3-diones as potential muscarinic agonists: synthesis, modeling and binding studies

Author

Barlocco, D., Francesca Fanelli, Cignarella, G., Villa, S., Cattabeni, F., Balduini, W., Cimino, M., and Benedetti, P. G.

Subjects
Cerebral Cortex, Models, Molecular, computational modeling, muscarinic receptors, Protein Conformation, Succinimides, Muscarinic Agonists, Receptors, Muscarinic, Drug design, GPCRs, Rats, Quinuclidinyl Benzilate, Animals, Carbachol, Computer Simulation, Spiro Compounds
Abstract

A series of 2-(acyl)amino-8-substituted-2,8-diazaspiro[4,5]decan-1,3-diones (5a-j), structurally related to the muscarinic agonist RS-86, was synthesized and compounds tested for their affinity towards muscarinic receptors. Though all compounds proved to be less active than the model in binding studies, only three derivatives (5a, b, c) being able to significantly displace 3H-QNB at mM concentration, their behaviour could be interpreted in terms of theoretical molecular descriptors computed on the basis of the suggestions coming from Molecular Dynamics simulations of ligand-receptor complexes.

Published
1996

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