2-Aroylindoles and 2-Aroylbenzofurans with N-Hydroxyacrylamide Substructures as a Novel Series of Rationally Designed Histone Deacetylase Inhibitors
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- 作者：Siavosh Mahboobi ; Andreas Sellmer ; Heymo Hö ; cher ; Christian Garhammer ; Herwig Pongratz ; Thomas Maier ; Thomas Ciossek ; Thomas Beckers
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：September 6, 2007
- 年：2007
- 卷：50
- 期：18
- 页码：4405 - 4418
- 全文大小：421K
- 年卷期：v.50,no.18(September 6, 2007)
- ISSN：1520-4804
文摘
Histone deacetylase (HDAC) inhibitors are considered to be drugs for targeted cancer therapy and second-generation HDIs are currently being tested in clinical trials. Here, we report on the synthesis and biologicalevaluation of a novel HDAC inhibitor scaffold with the hydroxamate Zn2+ complexing headgroup, selectedfrom the 2-aroylindol motif. Inhibition of nuclear extract HDAC and recombinant HDAC 1 as well asinduction of histone H3K9+14 hyperacetylation mediated by E-N-hydroxy-(2-aroylindole)acrylamides or E-N-hydroxy-(2-aroylbenzofuran)acrylamides were studied. Moreover, the cytotoxic activity, the effects on thecell cycle, and histone H3S10 phosphorylation of selected compounds were determined. By use of a panelof 24 different human tumor cell lines, mean IC50 values of the most potent analogues 6c and 7b were 0.75and 0.65 
M, respectively. The novel compounds were shown to be no substrates of the P-glycoproteindrug transporter. Comparable to N1-hydroxy-N8-phenyloctanediamide "2 (SAHA)", cells in the S phase ofthe cell cycle are depleted, with partial arrest in G1 and G2/M and finally induction of massive apoptosis.
M, respectively. The novel compounds were shown to be no substrates of the P-glycoproteindrug transporter. Comparable to N1-hydroxy-N8-phenyloctanediamide "2 (SAHA)", cells in the S phase ofthe cell cycle are depleted, with partial arrest in G1 and G2/M and finally induction of massive apoptosis.