Design, Synthesis, and Biological Evaluation of Stable Colchicine-Binding Site Tubulin Inhibitors 6-Aryl-2-benzoyl-pyridines as Potential Anticancer Agents

被引：41

作者：

Chen, Hao ^{[1
]}

Deng, Shanshan ^{[1
]}

Albadari, Najah ^{[1
]}

Yun, Mi-Kyung ^{[2
]}

Zhang, Sicheng ^{[1
]}

Li, Yong ^{[3
]}

Ma, Dejian ^{[1
]}

Parke, Deanna N. ^{[4
]}

Yang, Lei ^{[3
]}

Seagroves, Tiffany N. ^{[4
]}

White, Stephen W. ^{[2
]}

Miller, Duane D. ^{[1
]}

Li, Wei ^{[1
]}

机构：

[1] Univ Tennessee, Coll Pharm, Dept Pharmaceut Sci, Hlth Sci Ctr, Memphis, TN 38163 USA

[2] St Jude Childrens Res Hosp, Dept Struct Biol, Memphis, TN 38105 USA

[3] St Jude Childrens Res Hosp, Dept Chem Biol & Therapeut, Memphis, TN 38105 USA

[4] Univ Tennessee, Coll Med, Dept Pathol, Hlth Sci Ctr, Memphis, TN 38163 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2021年 / 64卷 / 16期

关键词：

MICROSOMAL STABILITY ASSAY; POLYMERIZATION; MICROTUBULES; RESISTANCE; ANALOGS;

D O I：

10.1021/acs.jmedchem.1c00715

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We previously reported a potent tubulin inhibitor CH-2-77. In this study, we optimized the structure of CH-2-77 by blocking metabolically labile sites and synthesized a series of CH-2-77 analogues. Two compounds, 40a and 60c, preserved the potency while improving the metabolic stability over CH-2-77 by 3- to 4-fold (46.8 and 29.4 vs 10.8 min in human microsomes). We determined the high-resolution X-ray crystal structures of 40a (resolution 2.3 angstrom) and 60c (resolution 2.6 angstrom) in complex with tubulin and confirmed their direct binding at the colchicine-binding site. In vitro, 60c maintained its mode of action by inhibiting tubulin polymerization and was effective against P-glycoprotein-mediated multiple drug resistance and taxol resistance. In vivo, 60c exhibited a strong inhibitory effect on tumor growth and metastasis in a taxol-resistant A375/TxR xenograft model without obvious toxicity. Collectively, this work showed that 60c is a promising lead compound for further development as a potential anticancer agent.

引用

页码：12049 / 12074

页数：26

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