Design, Synthesis, and Biological Evaluation of 1-Methyl-1,4-dihydroindeno[1,2-c]pyrazole Analogues as Potential Anticancer Agents Targeting Tubulin Colchicine Binding Site.

doi:10.1021/acs.jmedchem.6b00071

Paper

Design, Synthesis, and Biological Evaluation of 1-Methyl-1,4-dihydroindeno[1,2-c]pyrazole Analogues as Potential Anticancer Agents Targeting Tubulin Colchicine Binding Site.

Published 2016 · Yan-Na Liu, Jing-jing Wang, Ya-Ting Ji

Journal of medicinal chemistry

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52

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Abstract

By targeting a new binding region at the interface between αβ-tubulin heterodimers at the colchicine binding site, we designed a series of 7-substituted 1-methyl-1,4-dihydroindeno[1,2-c]pyrazoles as potential tubulin polymerization inhibitors. Among the compounds synthesized, 2-(6-ethoxy-3-(3-ethoxyphenylamino)-1-methyl-1,4-dihydroindeno[1,2-c]pyrazol-7-yloxy)acetamide 6a and 2-(6-ethoxy-3-(3-ethoxyphenylamino)-1-methyl-1,4-dihydroindeno[1,2-c]pyrazol-7-yloxy)-N-hydroxyacetamide 6n showed noteworthy low nanomolar potency against HepG2, Hela, PC3, and MCF-7 cancer cell lines. In mechanism studies, 6a inhibited tubulin polymerization and disorganized microtubule in A549 cells by binding to tubulin colchicine binding site. 6a arrested A549 cells in G2/M phase that was related to the alterations in the expression of cyclin B1 and p-cdc2. 6a induced A549 cells apoptosis through the activation of caspase-3 and PARP. In addition, 6a inhibited capillary tube formation in a concentration-dependent manner. In nonsmall cell lung cancer xenografts mouse model, 6a suppressed tumor growth by 59.1% at a dose of 50 mg/kg (ip) without obvious toxicity, indicating its in vivo potential as anticancer agent.

In Vitro Study

Study Snapshot

1-Methyl-1,4-dihydroindeno[1,2-c]pyrazole analogues show potential as anticancer agents by targeting tubulin colchicine binding site and inducing apoptosis in cancer cells without obvious toxicity.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Design, Synthesis, and Biological Evaluation of 1-Methyl-1,4-dihydroindeno[1,2-c]pyrazole Analogues as Potential Anticancer Agents Targeting Tubulin Colchicine Binding Site.

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References

Citations

Palladium-Mediated Bioorthogonal System for Prodrug Activation of N-Benzylbenzamide-Containing Tubulin Polymerization Inhibitors for the Treatment of Solid Tumors.

Prodrug 2b, 68.3-fold less cytotoxic than its parent compound, shows potential in inhibiting tumor growth when activated by palladium resins.

Discovery of novel quinazoline derivatives as tubulin polymerization inhibitors targeting the colchicine binding site with potential anti-colon cancer effects.

Compound Q19 shows potential as a promising colon cancer therapy targeting tubulin, with minimal toxic side effects and acceptable pharmacokinetic properties.

Redox‐Neutral Nickel‐Catalyzed Selective Hydroalkynylation of Internal Alkyne and Its Application in Anticancer Agent Discovery†

Nickel-catalyzed selective hydroalkynylation of internal alkynes can lead to novel anti-tumor compounds, such as 8a, with potential anti-tumor cell proliferation activity.

Design and synthesis of novel 3-amino-5-phenylpyrazole derivatives as tubulin polymerization inhibitors targeting the colchicine-binding site.

Compound 5b shows promising antitumor activity by targeting tubulin colchicine-binding sites, inhibiting cancer cell growth, migration, and angiogenesis without obvious toxicity.

Spectroscopic, DFT, molecular docking and anti-cancer studies of regioselectively designed 1-aryl-indenopyrazoles

The synthesized indenopyrazoles show potential as an effective and oral anti-cancer agent, with a comparable IC50 value to erlotinib and apoptosis induction.