Design, synthesis and biological evaluation of novel vicinal diaryl-substituted 1H-Pyrazole analogues of combretastatin A-4 as highly potent tubulin polymerization inhibitors

Romagnoli, Romeo; Oliva, Paola; Salvador, María Kimatrai; Camacho, M. Encarnación; Padroni, Chiara; Brancale, Andrea; Ferla, Salvatore; Hamel, Ernest; Ronca, Roberto; Grillo, Elisabetta; Bortolozzi, Roberta; Rruga, Fatlum; Mariotto, Elena; Viola, Giampietro

doi:10.1016/j.ejmech.2019.111577

Cited by 24 publications

(7 citation statements)

References 66 publications

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“…Romagnoli et al previously published a series of potent analogues in which CA-4's ethylene bridge is incorporated into 3,4-diaryl substituted 1H-pyrazoles (highlighted in blue, Figure 7) and tetrazoles [96,97]. This work was based on the work of Medarde and co-workers from 2005, who described 3,4-disubstitued pyrazole derivatives of CA-4.…”

Section: Pyrazole Analoguesmentioning

confidence: 99%

“…This preliminary data is particularly promising as neurotoxicity is a major limiting factor in the clinical use of antimitotic agents. Lead compound 39 was assessed in a mouse allograft tumour model using E0771 murine breast cancer cells and preliminary results show reduction in tumour burden comparable to CA-4P, with no toxic effects or weight loss [97].…”

Section: Pyrazole Analoguesmentioning

confidence: 99%

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Colchicine-Binding Site Inhibitors from Chemistry to Clinic: A Review

2020

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It is over 50 years since the discovery of microtubules, and they have become one of the most important drug targets for anti-cancer therapies. Microtubules are predominantly composed of the protein tubulin, which contains a number of different binding sites for small-molecule drugs. There is continued interest in drug development for compounds targeting the colchicine-binding site of tubulin, termed colchicine-binding site inhibitors (CBSIs). This review highlights CBSIs discovered through diverse sources: from natural compounds, rational design, serendipitously and via high-throughput screening. We provide an update on CBSIs reported in the past three years and discuss the clinical status of CBSIs. It is likely that efforts will continue to develop CBSIs for a diverse set of cancers, and this review provides a timely update on recent developments.

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Section: Pyrazole Analoguesmentioning

confidence: 99%

Section: Pyrazole Analoguesmentioning

confidence: 99%

Colchicine-Binding Site Inhibitors from Chemistry to Clinic: A Review

2020

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“…The tubulin polymerization inhibition IC 50 was found to be 0.35 μM, along with in vivo tumor growth inhibition at low doses (5 mg kg −1 ). 21 Sulfur-containing heterocycles have exhibited potential cytotoxic activity; thiazolidinone is one crucial example, evident from its presence in different molecules that have been examined as anticancer agents. 22 Given anticancer therapeutics, a thiazolidinone indole hybrid VIII displayed the highest cytotoxicity with an IC 50 value of 0.92 μM towards the HCT-15 cancer cell line among other synthesized compounds.…”

Section: Introductionmentioning

confidence: 99%

“…The tubulin polymerization inhibition IC 50 was found to be 0.35 μM, along with in vivo tumor growth inhibition at low doses (5 mg kg −1 ). 21…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis andin vitrocytotoxicity evaluation of indolo–pyrazoles grafted with thiazolidinone as tubulin polymerization inhibitors

et al. 2023

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“…Among these sites, only drugs that interact with the colchicine site on tubulin can inhibit the process of angiogenesis (formation of new blood vessels) [8,9,10,11,12,13,14]. Currently, various types of colchicine binding site inhibitors (CBSIs) have been developed [15,16,17,18,19,20]. However, there are no FDA-approved drugs of this class on the market, because of their toxicity.…”

Section: Introductionmentioning

confidence: 99%

Structure-Based Pharmacophore Design and Virtual Screening for Novel Tubulin Inhibitors with Potential Anticancer Activity

Zhou

Niu

2019

Molecules

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Tubulin inhibitors have been considered as potential drugs for cancer therapy. However, their drug resistance and serious side-effects are the main reasons for clinical treatment failure. Therefore, there is still an urgent need to develop effective therapeutic drugs. Herein, a structure-based pharmacophore model was developed based on the co-crystallized structures of the tubulin with a high resolution. The model including one hydrogen-bond acceptor feature, two aromatic features, and one hydrophobic feature was further validated using the Gunner–Henry score method. Virtual screening was performed by an integrated protocol that combines drug-likeness analysis, pharmacophore mapping, and molecular docking approaches. Finally, five hits were selected for biological evaluation. The results indicated that all these hits at the concentration of 40 μM showed an inhibition of more than 50% against five human tumor cells (MCF-7, U87MG, HCT-116, MDA-MB-231, and HepG2). Particularly, hit 1 effectively inhibited the proliferation of these tumor cells, with inhibition rates of more than 80%. The results of tubulin polymerization and colchicine-site competition assays suggested that hit 1 significantly inhibited tubulin polymerization by binding to the colchicine site. Thus, hit 1 could be used as a potential chemotherapeutic agent for cancer treatment. This work also demonstrated the potential of our screening protocol to identify biologically active compounds.

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Design, synthesis and biological evaluation of novel vicinal diaryl-substituted 1H-Pyrazole analogues of combretastatin A-4 as highly potent tubulin polymerization inhibitors

Cited by 24 publications

References 66 publications

Colchicine-Binding Site Inhibitors from Chemistry to Clinic: A Review

Colchicine-Binding Site Inhibitors from Chemistry to Clinic: A Review

Design, synthesis andin vitrocytotoxicity evaluation of indolo–pyrazoles grafted with thiazolidinone as tubulin polymerization inhibitors

Structure-Based Pharmacophore Design and Virtual Screening for Novel Tubulin Inhibitors with Potential Anticancer Activity

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