Angiogenesis, Anti-Tumor, and Anti-Metastatic Activity of Novel α-Substituted Hetero-Aromatic Chalcone Hybrids as Inhibitors of Microtubule Polymerization.

Moran Sun,Yuyang Wang,Qing Zhao,Yixin Zhang,Minghua Yuan,Yongtao Duan,Yongfang Yao

doi:10.3389/fchem.2021.766201

Moran Sun, Yuyang Wang + Show 5 more

Open Access

https://doi.org/10.3389/fchem.2021.766201

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Abstract

A library of new heteroaromatic ring-linked chalcone analogs were designed and synthesized of these, compound 7m with α-CH3 substitution and bearing a benzofuran ring, displaying the most potent activity, with IC50 values of 0.07–0.183 µM against three cancer cells. Its low cytotoxicity toward normal human cells and strong potency on drug-resistant cells revealed the possibility for cancer therapy. It also could moderately inhibit in vitro tubulin polymerization with an IC50 value of 12.23 µM, and the disruption of cellular architecture in MCF-7 cells was observed by an immunofluorescence assay. Cellular-based mechanism studies elucidated that 7m arrested the cell cycle at the G2/M phase and induced apoptosis by regulating the expression levels of caspases and PARP protein. Importantly, the compound 7 m was found to inhibit HUVEC tube formation, migration, and invasion in vitro. In vivo assay showed that 7m could effectively destroy angiogenesis of zebrafish embryos. Furthermore, our data suggested that treatment with 7m significantly reduced MCF-7 cell metastasis and proliferation in vitro and in zebrafish xenograft. Collectively, this work showed that chalcone hybrid 7m deserves further investigation as dual potential tubulin polymerization and angiogenesis inhibitor.

Highlights

Microtubules are composed of α- and β-tubulin heterodimers and served as key components of the eukaryotic cytoskeleton
A similar strategy was used in the preparation of chalcone 7 containing a methyl group at the α-position in modest yields as a mixture of geometrical isomers, which were separated by column chromatography
The chalcone hybrid 7m bearing a benzofuran ring in B-ring is most potent in 44 benzoheterocycle analogs

Summary

Introduction

Microtubules are composed of α- and β-tubulin heterodimers and served as key components of the eukaryotic cytoskeleton. Numerous microtubule-binding drugs have been used in therapeutic and palliative cancer chemotherapy regiments (Gigant et al, 2005; Chen et al, 2010; Li, 2012; Duan et al, 2016). Studies have shown that most microtubule-targeting agents have anti-angiogenic or vascular-disrupting activities or both Targeting tumor vasculature as a therapeutic approach has a compelling theoretical basis, which is complementary to other existing therapies (Tozer et al, 2005; Mckeage and Baguley, 2010; Greene et al, 2015). These compounds cause selective damage to tumor blood vessel, inducing

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