摘要

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.
原文英語
頁(從 - 到)667-677
頁數11
期刊European Journal of Medicinal Chemistry
150
DOIs
出版狀態已發佈 - 四月 25 2018

指紋

Hydroxamic Acids
Histone Deacetylase Inhibitors
Antineoplastic Agents
Protein Isoforms
Cells
Lung
Inhibitory Concentration 50
Cell Line
Leukemia
Proteins

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

引用此文

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title = "1-Aroylindoline-hydroxamic acids as anticancer agents, inhibitors of HSP90 and HDAC",
abstract = "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.",
keywords = "Cancer, Heat shock protein, Histone deacetylase inhibitors, Indoline",
author = "Ritu Ojha and Huang, {Han Li} and HuangFu, {Wei Chun} and Wu, {Yi Wen} and Kunal Nepali and Lai, {Mei Jung} and Su, {Chih Jou} and Sung, {Ting Yi} and Chen, {Yi Lin} and Pan, {Shiow Lin} and Liou, {Jing Ping}",
note = "Copyright {\circledC} 2018. Published by Elsevier Masson SAS.",
year = "2018",
month = "4",
day = "25",
doi = "10.1016/j.ejmech.2018.03.006",
language = "English",
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journal = "European Journal of Medicinal Chemistry",
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TY - JOUR

T1 - 1-Aroylindoline-hydroxamic acids as anticancer agents, inhibitors of HSP90 and HDAC

AU - Ojha, Ritu

AU - Huang, Han Li

AU - HuangFu, Wei Chun

AU - Wu, Yi Wen

AU - Nepali, Kunal

AU - Lai, Mei Jung

AU - Su, Chih Jou

AU - Sung, Ting Yi

AU - Chen, Yi Lin

AU - Pan, Shiow Lin

AU - Liou, Jing Ping

N1 - Copyright © 2018. Published by Elsevier Masson SAS.

PY - 2018/4/25

Y1 - 2018/4/25

N2 - 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.

AB - 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.

KW - Cancer

KW - Heat shock protein

KW - Histone deacetylase inhibitors

KW - Indoline

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U2 - 10.1016/j.ejmech.2018.03.006

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M3 - Article

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