Mahboobi, Siavosh and Sellmer, Andreas and Hoecher, Heymo and Garhammer, Christian and Pongratz, Herwig and Maier, Thomas and Ciossek, Thomas and Beckers, Thomas (2007) 2-aroylindoles and 2-aroylbenzofurans with N-hydroxyacrylamide substructures as a novel series of rationally designed histone deacetylase inhibitors. JOURNAL OF MEDICINAL CHEMISTRY, 50 (18). pp. 4405-4418. ISSN 0022-2623, 1520-4804
Full text not available from this repository. (Request a copy)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 Zn2+ complexing headgroup, selected from the 2-aroylindol motif. Inhibition of nuclear extract HDAC and recombinant HDAC I as well as induction of histone H3K(9+14) hyperacetylation mediated by E-N-hydroxy-(2-aroylindole)acrylamides or E-Nhydroxy-(2-aroylbenzofuran)acrylamides were studied. Moreover, the cytotoxic activity, the effects on the cell cycle, and historic H3S(10) phosphorylation of selected compounds were determined. By use of a panel of 24 different human tumor cell lines, mean IC50 values of the most potent analogues 6c and 7b were 0.75 and 0.65 mu M, 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ANTITUMOR-ACTIVITY; CANCER-THERAPY; PHASE-I; GROWTH; PROLIFERATION; TRANSCRIPTION; SENSITIVITY; REPRESSION; KINASE; TUMORS; |
| Subjects: | 500 Science > 540 Chemistry & allied sciences |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 01 Dec 2020 07:41 |
| Last Modified: | 01 Dec 2020 07:41 |
| URI: | https://pred.uni-regensburg.de/id/eprint/32213 |
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