Click chemistry-assisted synthesis of triazolo linked podophyllotoxin conjugates as tubulin polymerization inhibitors,RSC Medicinal Chemistry

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Click chemistry-assisted synthesis of triazolo linked podophyllotoxin conjugates as tubulin polymerization inhibitors
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2017-07-18 00:00:00 , DOI: 10.1039/c7md00273d
M. V. P. S. Vishnuvardhan _{1,

2,

3,

4} , Saidi Reddy V. _{1,

2,

3,

4} , Kunta Chandrasekhar _{1,

2,

3,

4} , V. Lakshma Nayak _{1,

2,

3,

4} , Ibrahim Bin Sayeed _{1,

2,

3,

4} , Abdullah Alarifi _{5,

6,

7,

8,

9} , Ahmed Kamal _{1,

2,

3,

4,

5}

Affiliation

A series of new triazolo linked 4β-amidopodophyllotoxin conjugates (9a–l) were synthesized using click chemistry and evaluated for their antitumor activity against four human cancer cell lines. Among them, two compounds (9c and 9j) showed significant anticancer activity with IC₅₀ values of 0.9 and 0.07 μM, respectively. Biological studies are conducted into the cell-cycle distribution of these conjugates inducing G2/M-phase arrest, apart from an increase in the levels of caspase-3 proteins, followed by apoptotic cell death. A tubulin polymerization assay analysis showed that these compounds effectively inhibit microtubule assembly in HeLa cells and, moreover, Hoechst 33258 and Immunohistochemistry staining suggest that these compounds induce cell death by apoptosis. The docking studies showed that compounds 9c and 9j interact and bind efficiently with the tubulin protein at the colchicine site.

中文翻译：

单击化学辅助合成的三唑连接的鬼臼毒素缀合物作为微管蛋白聚合抑制剂

使用点击化学方法合成了一系列新的三唑并连接的4β-酰胺基鬼臼毒素偶联物（9a–l），并评估了它们对四种人类癌细胞系的抗肿瘤活性。其中，两种化合物（9c和9j）对IC ₅₀表现出显着的抗癌活性分别为0.9和0.07μM。对这些缀合物诱导G2 / M期阻滞的细胞周期分布进行了生物学研究，除了caspase-3蛋白水平的升高外，还有凋亡细胞的死亡。微管蛋白聚合测定分析表明，这些化合物可有效抑制HeLa细胞中的微管装配，此外，Hoechst 33258和免疫组织化学染色表明，这些化合物可通过凋亡诱导细胞死亡。对接研究表明，化合物9c和9j在秋水仙碱位点与微管蛋白有效相互作用并结合。

更新日期：2017-08-04

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