Small-Molecule Inhibitors of Histone Acetyltransferase Activity: Identification and Biological Properties
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- 作者：Antonello Mai ; Dante Rotili ; Domenico Tarantino ; Prisca Ornaghi ; Federica Tosi ; Caterina Vicidomini ; Gianluca Sbardella ; Angela Nebbioso ; Marco Miceli ; Lucia Altucci ; Patrizia Filetici
- 刊名：Journal of Medicinal Chemistry
- 出版年：2006
- 出版时间：November 16, 2006
- 年：2006
- 卷：49
- 期：23
- 页码：6897 - 6907
- 全文大小：434K
- 年卷期：v.49,no.23(November 16, 2006)
- ISSN：1520-4804
文摘
Starting from a yeast phenotypic screening performed on 21 compounds, we described the identification oftwo small molecules (9 and 18) able to significantly reduce the S. cerevisiae cell growth, thus miming theeffect of GCN5 deletion mutant. Tested on a GCN5-dependent gene transcription assay, compounds 9 and18 gave a high reduction of the reporter activity. In S. cerevisiae histone H3 terminal tails assay, the H3acetylation levels were highly reduced by treatment with 0.6-1 mM 9, while 18 was effective only at 1.5mM. In human leukemia U937 cell line, at 1 mM 9 and 18 showed effects on cell cycle (arrest in G1 phase,9), apoptosis (9), and granulocytic differentiation (18). When tested on U937 cell nuclear extracts to evaluatetheir histone acetyltransferase (HAT) inhibitory action, both compounds were able to reduce the enzymeactivity when used at 500 
M. Another quinoline, compound 22, was synthesized with the aim to improvethe activity observed with 9 and 18. Tested in the HAT assay, 22 was able to reduce the HAT catalyticaction at 50 and 25 M, thereby being comparable to anacardic acid, curcumin, and MB-3 used as references.Finally, in U937 cells, compounds 9 and 18 used at 2.5 mM were able to reduce the extent of the acetylationlevels of histone H3 (9) and 
-tubulin (9 and 18). In the same assay, 22 at lower concentration (100 M)showed the same hypoacetylating effects with both histone and non-histone substrates.
M. Another quinoline, compound 22, was synthesized with the aim to improvethe activity observed with 9 and 18. Tested in the HAT assay, 22 was able to reduce the HAT catalyticaction at 50 and 25 M, thereby being comparable to anacardic acid, curcumin, and MB-3 used as references.Finally, in U937 cells, compounds 9 and 18 used at 2.5 mM were able to reduce the extent of the acetylationlevels of histone H3 (9) and -tubulin (9 and 18). In the same assay, 22 at lower concentration (100 M)showed the same hypoacetylating effects with both histone and non-histone substrates.