1-Aroylindoline-hydroxamic acids as anticancer agents, inhibitors of HSP90 and HDAC
| Autor: | Kunal Nepali, Wei Chun HuangFu, Shiow Lin Pan, Mei Jung Lai, Ritu Ojha, Yi Wen Wu, Han Li Huang, Jing Ping Liou, Chih Jou Su, Ting Yi Sung, Yi Lin Chen |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Gene isoform Indoles HL60 Mutant Antineoplastic Agents Hydroxamic Acids Histone Deacetylases Hsp90 inhibitor Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cell Line Tumor Drug Discovery Humans Cytotoxic T cell HSP90 Heat-Shock Proteins Cell Proliferation Pharmacology Dose-Response Relationship Drug Molecular Structure biology Chemistry Organic Chemistry General Medicine HDAC6 Hsp90 Histone Deacetylase Inhibitors 030104 developmental biology Cell culture 030220 oncology & carcinogenesis Cancer research biology.protein Drug Screening Assays Antitumor |
| Zdroj: | European Journal of Medicinal Chemistry. 150:667-677 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2018.03.006 |
| Popis: | A series of 1-aroylindoline-hydroxamic acids have been synthesized in the present study. The results of the biological evaluation led to the identification of compound 12 as dual HDAC6/HSP90 inhibitor. Compound 12 displayed striking inhibitory effects towards the HDAC6 isoform and HSP 90 protein with IC50 values of 1.15 nM (HDAC6) and 46.3 nM (HSP90). Compound 12 also exhibited 113, 139 and 246 fold higher selectivity for HDAC6 over HDAC 1, HDAC 3 and HDAC 8 isoforms and was endowed with significant cytotoxic effects with GI50 values ranging 1.04–1.61 μM against lung A549, colorectal HCT116, leukemia HL60, and EGFR T790M mutant lung H1975 cell lines. Another interesting finding of the study was substantial cytotoxic effects of compounds particularly against lung H1975 (NSCLC) cell lines with IC50 = 0.26 μM which may be mediated through HSP90 inhibition. Compound 8 as such was devoid of HDAC inhibitory activity. |
| Databáze: | OpenAIRE |
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