Discovery of Biarylaminoquinazolines as Novel Tubulin Polymerization Inhibitors

Marzaro, Giovanni; Coluccia, Antonio; Ferrarese, Alessandro; Brun, Paola; Castagliuolo, Ignazio; Conconi, Maria Teresa; Regina, Giuseppe La; Bai, Ruoli; Silvestri, Romano; Hamel, Ernest; Chilin, Adriana

doi:10.1021/jm500034j

Cited by 28 publications

(18 citation statements)

References 31 publications

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“…It should be noted that the literature data on the synthesis of aminophenylpyrroles are scarce. For instance, 2‐(3‐aminophenyl)pyrrole ( 2 a ) was prepared from 3‐bromoaniline, protected as ethyl carbamate, which was condensed with N ‐Boc‐2‐pyrroleboronic acid via Suzuki coupling with subsequent deprotection at both amine functions in an alkaline medium . 2‐(4‐Aminophenyl)pyrrole ( 2 b ) was obtained from 4‐aminoacetophenone oxime and 1,2‐dichloroethane .…”

Section: Resultsmentioning

confidence: 99%

Environment‐Responsive 8‐CF₃‐BODIPY Dyes with Aniline Groups at the 3 Position: Synthesis, Optical Properties and RI‐CC2 Calculations

et al. 2017

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The spectroscopic and the photophysical properties of isomeric environment-sensitive BODIPYd erivatives in different solvents are reported. The simultaneous presence of the stronge lectron-acceptorC F 3 and electron-donor NH 2 group in the structure of BODIPY,a sw ell as the positiono f the NH 2 group on the aryl ring, showedasignificante ffect on the spectroscopic and fluorescence characteristics of the BODIPY chromophore, both experimentally and theoretically. The comparison of meta and para derivatives (1a and 1b) shows that, in both cases, they have av ery low quantum yield (F f )a nd fluorescencel ifetime (t f )i nt he solvents used (except for n-hexane), therefore, they are potentially suitable as turn-onf luorescences ensors. The twisted intramolecular charge transfer (TICT) mechanism was adopted to explain solvate-induced fluorescence quenching. Besides this, there is as trong pH dependence on the photophysical behavior of the two isomers, which could also lead to applications as pH sensors. On the other hand, only 1a can be au seful probe for CO 2 sensing.O wing to aw eaker electron-donor character of the NHCOMe group in comparison with the NH 2 group, the position of the fluorescence "off-on" threshold of BODIPY 1c and 1d is shifted to the side of more polar solvents than for 1a and 1b.

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Section: Resultsmentioning

confidence: 99%

Environment‐Responsive 8‐CF₃‐BODIPY Dyes with Aniline Groups at the 3 Position: Synthesis, Optical Properties and RI‐CC2 Calculations

et al. 2017

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“…[13][14][15] In addition, biaryl moieties have been frequently observed in the development of anti-tubulin agents. [15][16][17] Compound 6, with both benzenesulfonamide and biaryl moieties, was found in our previous study to have remarkable antiproliferative activity. 15 Literature surveys indicate that the N-sulfonyl-aminobiaryl moiety has been comprehensively included in various heterocycles such as carbazole 18 , phenanthridinones, and phenanthridines 19,20 ; but little investigation of its biological potential has been reported., This study therefore, is aimed at synthesis of a series of Nsulfonyl-aminobiaryl derivatives (7-26) and assays of their activity against the growth of cancer cells.…”

Section: Introductionmentioning

confidence: 96%

N-Sulfonyl-aminobiaryls as Antitubulin Agents and Inhibitors of Signal Transducers and Activators of Transcription 3 (STAT3) Signaling

et al. 2015

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A series of N-sulfonyl-aminobiaryl derivatives have been examined as novel antitubulin agents. Compound 21 [N-(4'-cyano-3'-fluoro-biphenyl-2-yl)-4-methoxy-benzenesulfonamide] exhibits remarkable antiproliferative activity against four cancer cell lines (pancreatic AsPC-1, lung A549, liver Hep3B, and prostate PC-3) with a mean GI50 value of 57.5 nM. Additional assays reveal that 21 inhibits not only tubulin polymerization but also the phosphorylation of STAT3 inhibition with an IC50 value of 0.2 μM. Four additional compounds (8, 10, 19, and 35) are also able to inhibit this phosphorylation. This study describes novel N-sulfonyl-aminobiaryl (biaryl-benzenesulfonamides) as potent anticancer agents targeting both STAT3 and tubulin.

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“…In the second example [ 27 ], all designed molecules interacted with EGFR, FGFR1 and ABL1 except one selectively targeted tubulin. All the non-selective interactions were predicted by the most similar exemplar of CHEMBL56802 [for the detailed list, see Additional file 7 ].…”

Section: Resultsmentioning

confidence: 99%

Ligand cluster-based protein network and ePlatton, a multi-target ligand finder

Shi

2016

J Cheminform

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BackgroundSmall molecules are information carriers that make cells aware of external changes and couple internal metabolic and signalling pathway systems with each other. In some specific physiological status, natural or artificial molecules are used to interact with selective biological targets to activate or inhibit their functions to achieve expected biological and physiological output. Millions of years of evolution have optimized biological processes and pathways and now the endocrine and immune system cannot work properly without some key small molecules. In the past thousands of years, the human race has managed to find many medicines against diseases by trail-and-error experience. In the recent decades, with the deepening understanding of life and the progress of molecular biology, researchers spare no effort to design molecules targeting one or two key enzymes and receptors related to corresponding diseases. But recent studies in pharmacogenomics have shown that polypharmacology may be necessary for the effects of drugs, which challenge the paradigm, ‘one drug, one target, one disease’. Nowadays, cheminformatics and structural biology can help us reasonably take advantage of the polypharmacology to design next-generation promiscuous drugs and drug combination therapies.Results234,591 protein–ligand interactions were extracted from ChEMBL. By the 2D structure similarity, 13,769 ligand emerged from 156,151 distinct ligands which were recognized by 1477 proteins. Ligand cluster- and sequence-based protein networks (LCBN, SBN) were constructed, compared and analysed. For assisting compound designing, exploring polypharmacology and finding possible drug combination, we integrated the pathway, disease, drug adverse reaction and the relationship of targets and ligand clusters into the web platform, ePlatton, which is available at http://www.megabionet.org/eplatton.ConclusionsAlthough there were some disagreements between the LCBN and SBN, communities in both networks were largely the same with normalized mutual information at 0.9. The study of target and ligand cluster promiscuity underlying the LCBN showed that light ligand clusters were more promiscuous than the heavy one and that highly connected nodes tended to be protein kinases and involved in phosphorylation. ePlatton considerably reduced the redundancy of the ligand set of targets and made it easy to deduce the possible relationship between compounds and targets, pathways and side effects. ePlatton behaved reliably in validation experiments and also fast in virtual screening and information retrieval.Graphical abstractCluster exemplars and ePlatton’s mechanism.Electronic supplementary materialThe online version of this article (doi:10.1186/s13321-016-0135-5) contains supplementary material, which is available to authorized users.

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Discovery of Biarylaminoquinazolines as Novel Tubulin Polymerization Inhibitors

Cited by 28 publications

References 31 publications

Environment‐Responsive 8‐CF₃‐BODIPY Dyes with Aniline Groups at the 3 Position: Synthesis, Optical Properties and RI‐CC2 Calculations

Environment‐Responsive 8‐CF₃‐BODIPY Dyes with Aniline Groups at the 3 Position: Synthesis, Optical Properties and RI‐CC2 Calculations

N-Sulfonyl-aminobiaryls as Antitubulin Agents and Inhibitors of Signal Transducers and Activators of Transcription 3 (STAT3) Signaling

Ligand cluster-based protein network and ePlatton, a multi-target ligand finder

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Discovery of Biarylaminoquinazolines as Novel Tubulin Polymerization Inhibitors

Cited by 28 publications

References 31 publications

Environment‐Responsive 8‐CF3‐BODIPY Dyes with Aniline Groups at the 3 Position: Synthesis, Optical Properties and RI‐CC2 Calculations

Environment‐Responsive 8‐CF3‐BODIPY Dyes with Aniline Groups at the 3 Position: Synthesis, Optical Properties and RI‐CC2 Calculations

N-Sulfonyl-aminobiaryls as Antitubulin Agents and Inhibitors of Signal Transducers and Activators of Transcription 3 (STAT3) Signaling

Ligand cluster-based protein network and ePlatton, a multi-target ligand finder

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Product

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Environment‐Responsive 8‐CF₃‐BODIPY Dyes with Aniline Groups at the 3 Position: Synthesis, Optical Properties and RI‐CC2 Calculations

Environment‐Responsive 8‐CF₃‐BODIPY Dyes with Aniline Groups at the 3 Position: Synthesis, Optical Properties and RI‐CC2 Calculations