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.

LanguageEnglish
Pages667-677
Number of pages11
JournalEuropean Journal of Medicinal Chemistry
Volume150
DOIs
Publication statusPublished - Apr 25 2018

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

Keywords

  • Cancer
  • Heat shock protein
  • Histone deacetylase inhibitors
  • Indoline

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

1-Aroylindoline-hydroxamic acids as anticancer agents, inhibitors of HSP90 and HDAC. / Ojha, Ritu; Huang, Han Li; HuangFu, Wei Chun; Wu, Yi Wen; Nepali, Kunal; Lai, Mei Jung; Su, Chih Jou; Sung, Ting Yi; Chen, Yi Lin; Pan, Shiow Lin; Liou, Jing Ping.

In: European Journal of Medicinal Chemistry, Vol. 150, 25.04.2018, p. 667-677.

Research output: Contribution to journalArticle

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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

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