Discovery of degradable niclosamide derivatives able to specially inhibit small cell lung cancer (SCLC)

文献类型： 外文期刊

第一作者： He, XingGang

作者： He, XingGang;He, XingGang;Li, MaoLin;Zhou, Wen;Zhou, Wen;Ye, WenChong

作者机构：

关键词： Discovery; Niclosamide; Water-solubility; Anti-SCLC; Selectivity

期刊名称：BIOORGANIC CHEMISTRY （ 影响因子：5.275； 五年影响因子：5.252 ）

ISSN： 0045-2068

年卷期： 2021 年 107 卷

页码：

收录情况： SCI

摘要： Small cell lung cancer (SCLC) is exceedingly tough to treat and easy to develop resistance upon long use of the first-line drug carboplatin or radiotherapy. Novel medicines effective and specific against SCLC are greatly needed. Herein, we focused on the discovery of such a medicine by exploring a drug niclosamide with repurposing strategy. Initial screening efforts revealed that niclosamide, an anthelmintic drug, possessed the in vitro anticancer activity and an obvious sensitivity towards SCLC. This observation inspired the evaluation for two different kinds of niclosamide derivatives. 2 with a degradable ester as a linker exhibited the comparable activity but slightly inferior selectivity to SCLC, by contrast, the cytotoxicities of 4 and 5 with non-degradable ether linkages completely disappeared, clearly validating the importance of 2-free hydroxyl group or 2-hydroxyl group released in the antitumor activity. Mechanism study unfolded that, similar to niclosamide, 2 inhibited growth of cancer cells via p 53 activation and subsequent underwent cytochrome c dependent apoptosis. Further structural modification to afford phosphate sodium 8 with significantly enhanced aqueous solubility (22.1 mg/mL) and a good selectivity towards SCLC demonstrated more promising druggability profiles. Accordingly, niclosamide as an attractive lead hold a huge potential for developing targeted anti-SCLC drugs.

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