2-aroylindoles and 2-aroylbenzofurans with N-hydroxyacrylamide substructures as a novel series of rationally designed histone deacetylase inhibitors.

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Mahboobi S, Sellmer A, Hocher H, Garhammer C, Pongratz H, Maier T, Ciossek T, Beckers T

2-aroylindoles and 2-aroylbenzofurans with N-hydroxyacrylamide substructures as a novel series of rationally designed histone deacetylase inhibitors.

J Med Chem. 2007 Sep 6;50(18):4405-18. Epub 2007 Aug 11.

PubMed ID

17691763 [ View in PubMed

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Abstract

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 biological evaluation of a novel HDAC inhibitor scaffold with the hydroxamate Zn(2+) complexing headgroup, selected from the 2-aroylindol motif. Inhibition of nuclear extract HDAC and recombinant HDAC 1 as well as induction of histone H3K(9+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 the cell cycle, and histone H3S(10) phosphorylation of selected compounds were determined. By use of a panel of 24 different human tumor cell lines, mean IC(50) values of the most potent analogues 6c and 7b were 0.75 and 0.65 microM, respectively. The novel compounds were shown to be no substrates of the P-glycoprotein drug transporter. Comparable to N(1)-hydroxy-N(8)-phenyloctanediamide "2 (SAHA)", cells in the S phase of the cell cycle are depleted, with partial arrest in G1 and G2/M and finally induction of massive apoptosis.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Vorinostat	Histone deacetylase 1	IC 50 (nM)	20	N/A	N/A	Details