Pérez-Balado Carlos, Nebbioso Angela, Rodríguez-Graña Paula, Minichiello Annunziata, Miceli Marco, Altucci Lucia, de Lera Angel R
Departamento de Química Orgánica, Universidade de Vigo, Lagoas-Marcosende, 36310 Vigo, Spain.
J Med Chem. 2007 May 17;50(10):2497-505. doi: 10.1021/jm070028m. Epub 2007 Apr 21.
A novel synthetic route to the cyclostellettamines 1 using as the key step a microwave-mediated macrocyclic ring-closing metathesis of precursors bispyridinium dienes 10 followed by catalytic hydrogenation has been developed. 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 10a inhibited isoforms HDAC2 and HDAC3. Cell cycle analysis, cell differentiation, and apoptosis as well as evaluation of the acetylation status of H3 lysine tails, up-regulation of p21WAF1/CIP1, and alpha-tubulin acetylation induced by the dienes 10 and cyclostellettamines 1 were also carried out on the human leukemia U937 cell line. These enzymatic and functional assays suggest that 10b is a HDAC1-selective inhibitor and 10a is a HDAC subclass IIa-selective inhibitor.
已开发出一种新颖的合成环蛇毒素胺1的路线，该路线以微波介导的前体双吡啶二烯10的大环闭环复分解反应为关键步骤，随后进行催化氢化。开链双吡啶二烯10显示出比天然产物一致更高的组蛋白脱乙酰酶（HDAC）抑制效力。二烯10b抑制HDAC1且对HDAC4无活性，而10a对HDAC1显示出弱抑制且对HDAC4具有更高活性。10b和10a均未抑制HDAC2和HDAC3亚型。还对人白血病U937细胞系进行了细胞周期分析、细胞分化和凋亡以及对H3赖氨酸尾部乙酰化状态的评估、p21WAF1/CIP1的上调以及由二烯10和环蛇毒素胺1诱导的α-微管蛋白乙酰化。这些酶促和功能测定表明，10b是一种HDAC1选择性抑制剂，10a是一种HDAC IIa亚类选择性抑制剂。
