Discovery of degradable niclosamide derivatives able to specially inhibit small cell lung cancer (SCLC)
| Autor: | MaoLin Li, XingGang He, Wen Zhou, Wenchong Ye |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Drug
Lung Neoplasms Cell Survival media_common.quotation_subject Transplantation Heterologous Druggability Drug Evaluation Preclinical Antineoplastic Agents 01 natural sciences Biochemistry chemistry.chemical_compound Mice Cell Line Tumor Drug Discovery medicine Animals Humans Molecular Biology Niclosamide media_common Mice Inbred BALB C biology 010405 organic chemistry Chemistry Cytochrome c Organic Chemistry Small Cell Lung Carcinoma In vitro Carboplatin respiratory tract diseases 0104 chemical sciences 010404 medicinal & biomolecular chemistry Solubility Apoptosis Cancer cell Cancer research biology.protein Drug Screening Assays Antitumor medicine.drug |
| Zdroj: | Bioorganic chemistry. 107 |
| ISSN: | 1090-2120 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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