Bispyridinium Dienes: Histone Deacetylase Inhibitors with Selective Activities
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- 作者：Carlos Pé ; rez-Balado ; Angela Nebbioso ; Paula Rodrí ; guez-Grañ ; a ; Annunziata Minichiello ; Marco Miceli ; Lucia Altucci ; ; ; Á ; ngel R. de Lera
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：May 17, 2007
- 年：2007
- 卷：50
- 期：10
- 页码：2497 - 2505
- 全文大小：301K
- 年卷期：v.50,no.10(May 17, 2007)
- ISSN：1520-4804
文摘
A novel synthetic route to the cyclostellettamines 1 using as the key step a microwave-mediated macrocyclicring-closing metathesis of precursors bispyridinium dienes 10 followed by catalytic hydrogenation has beendeveloped. The open-chain bispyridinium dienes 10 showed uniformly higher histone deacetylase (HDAC)inhibitory potency than the natural products. Diene 10b inhibited HDAC1 and was inactive on HDAC4,whereas 10a showed a weak inhibition of HDAC1 and a higher activity on HDAC4. Neither 10b nor 10ainhibited isoforms HDAC2 and HDAC3. Cell cycle analysis, cell differentiation, and apoptosis as well asevaluation of the acetylation status of H3 lysine tails, up-regulation of p21WAF1/CIP1, and 
fchars/alpha.gif" BORDER=0>-tubulin acetylationinduced by the dienes 10 and cyclostellettamines 1 were also carried out on the human leukemia U937 cellline. These enzymatic and functional assays suggest that 10b is a HDAC1-selective inhibitor and 10a is aHDAC subclass IIa-selective inhibitor.
fchars/alpha.gif" BORDER=0>-tubulin acetylationinduced by the dienes 10 and cyclostellettamines 1 were also carried out on the human leukemia U937 cellline. These enzymatic and functional assays suggest that 10b is a HDAC1-selective inhibitor and 10a is aHDAC subclass IIa-selective inhibitor.