1-Phenyl-dihydrobenzoindazoles as novel colchicine site inhibitors: Structural basis and antitumor efficacy

Jiang, Jun-Hang; Zhang, Hao; Wang, Chongqing; Zhang, Qingsen; Fang, Shaoyu; Zhou, Ruolan; Hu, Jian; Zhu, Jin; Zhou, Youjun; Luo, Cheng; Zheng, Canhui

doi:10.1016/j.ejmech.2019.04.040

Cited by 12 publications

(4 citation statements)

References 29 publications

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“…3) against A549 cell lines (IC50 = 0.12 μM) were much better than the control colchicine (IC50 = 1.17 μM). Jiang et al discovered novel and effective trimethoxyphenyl azole derivatives as tubulin inhibitors [47], in which amino substituted compound 35 (Fig. 3) showed IC50 values of 1 nM for both human colon cancer cell lines COLO205 and HCT-116 cells with IC50 values of 1.6 μM for inhibiting microtubule polymerization.…”

Section: Trimethoxyphenyl or Its Analogue Moiety As The Crucial Pharm...mentioning

confidence: 99%

An Update on the Recent Advances and Discovery of Novel Tubulin Colchicine Binding Inhibitors

Weng

Zhu

et al. 2023

Future Med. Chem.

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Microtubules, formed by α- and β-tubulin heterodimer, are considered as a major target to prevent the proliferation of tumor cells. Microtubule-targeted agents have become increasingly effective anticancer drugs. However, due to the relatively sophisticated chemical structure of taxane and vinblastine, their application has faced numerous obstacles. Conversely, the structure of colchicine binding site inhibitors (CBSIs) is much easier to be modified. Moreover, CBSIs have strong antiproliferative effect on multidrug-resistant tumor cells and have become the mainstream research orientation of microtubule-targeted agents. This review focuses mainly on the recent advances of CBSIs during 2017–2022, attempts to depict their biological activities to analyze the structure–activity relationships and offers new perspectives for designing next generation of novel CBSIs.

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Section: Trimethoxyphenyl or Its Analogue Moiety As The Crucial Pharm...mentioning

confidence: 99%

An Update on the Recent Advances and Discovery of Novel Tubulin Colchicine Binding Inhibitors

Weng

Zhu

et al. 2023

Future Med. Chem.

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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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“…Among recently reported examples, the dihydronaphthalene and benzosuberene derivatives ( 2 and 3 , respectively, Figure 1A) have shown antiproliferative activity at the sub nM range [20]. Very recently, Jiang, J. et al [21] described a novel 1-phenyl-dihydrobenzoindazole ( 4 , Figure 1A) with a locked conformation, that inhibited tubulin polymerization with an IC 50 of 1.6 μM and showed antitumor properties against a human colon cancer cell line with an IC 50 value of 1 nM. In both series the presence of an amino group on ring B is meant to mimic the phenolic OH of CA-4 and this amino group has been used for the synthesis of prodrugs thereof [20,21].…”

Section: Introductionmentioning

confidence: 99%

“…Very recently, Jiang, J. et al [21] described a novel 1-phenyl-dihydrobenzoindazole ( 4 , Figure 1A) with a locked conformation, that inhibited tubulin polymerization with an IC 50 of 1.6 μM and showed antitumor properties against a human colon cancer cell line with an IC 50 value of 1 nM. In both series the presence of an amino group on ring B is meant to mimic the phenolic OH of CA-4 and this amino group has been used for the synthesis of prodrugs thereof [20,21]. In addition, in all cases a trimethoxyphenyl is present as ring A (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of New 6-Nitro and 6-Amino-3,3a,4,5-Tetrahydro-2H-Benzo[g]indazole Derivatives: Antiproliferative and Antibacterial Activity

et al. 2019

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New substituted benzo[g]indazoles functionalized with a 6-nitro and 6-amino groups have been synthesized by the reaction of benzylidene tetralones with hydrazine in acetic acid. The resulting conformationally-constrained compounds were evaluated for their antiproliferative activity against selected cancer cell lines. The nitro-based indazoles 11a, 11b, 12a and 12b have shown IC50 values between 5–15 μM against the lung carcinoma cell line NCI-H460. Moreover, the nitro compounds were tested for antibacterial activity where compounds 12a and 13b have shown MIC values of 250 and 62.5 μg/mL against N. gonorrhoeae with no hemolytic activity in human red blood cells (RBC).

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1-Phenyl-dihydrobenzoindazoles as novel colchicine site inhibitors: Structural basis and antitumor efficacy

Cited by 12 publications

References 29 publications

An Update on the Recent Advances and Discovery of Novel Tubulin Colchicine Binding Inhibitors

An Update on the Recent Advances and Discovery of Novel Tubulin Colchicine Binding Inhibitors

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

Design and Synthesis of New 6-Nitro and 6-Amino-3,3a,4,5-Tetrahydro-2H-Benzo[g]indazole Derivatives: Antiproliferative and Antibacterial Activity

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