An aldol-based build/couple/pair strategy for the synthesis of medium- and large-sized rings: discovery of macrocyclic histone deacetylase inhibitors.
An aldol-based build/couple/pair strategy for the synthesis of medium- and large-sized rings: discovery of macrocyclic histone deacetylase inhibitors.
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DOI：
10.1021/ja105119r
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发表时间：
2010-12-01
影响因子：
15
通讯作者：
Foley, Michael A.
中科院分区：
文献类型：
--
作者：
Marcaurelle, Lisa A.;Comer, Eamon;Dandapani, Sivaraman;Duvall, Jeremy R.;Gerard, Baudouin;Kesavan, Sarathy;Lee, Maurice D.;Liu, Haibo;Lowe, Jason T.;Marie, Jean-Charles;Mulrooney, Carol A.;Pandya, Bhaumik A.;Rowley, Ann;Ryba, Troy D.;Suh, Byung-Chul;Wei, Jingqiang;Young, Damian W.;Akella, Lakshmi B.;Ross, Nathan T.;Zhang, Yan-Ling;Fass, Daniel M.;Reis, Surya A.;Zhao, Wen-Ning;Haggarty, Stephen J.;Palmer, Michelle;Foley, Michael A.
应用基于羟醛的“构建/耦合/配对”（B/C/P）策略来生成一系列立体化学和骨架多样化的小分子。在构建阶段，进行了一系列不对称顺式和反式醇醛反应，以产生 Boc 保护的 γ-氨基酸的四种立体异构体。此外，还生成了 O-PMB 保护的丙氨醇的两种立体异构体，以提供手性胺偶联伴侣。在偶联步骤中，通过偶联手性酸和胺结构单元合成了八种立体异构酰胺。随后酰胺被还原生成相应的仲胺。在配对相中，采用三种不同的反应来实现分子内成环过程，即：亲核芳香取代（SNAr）、Huisgen [3+2]环加成和闭环复分解（RCM）。尽管存在一些立体化学依赖性，但成环反应经过优化，可以以良好至优异的产率进行，提供尺寸范围从 8 元环到 14 元环的各种骨架。 RCM 配对反应产生的支架在固相上多样化，产生 14,400 成员的大环内酰胺库。通过对该文库的筛选，发现了一类新型组蛋白脱乙酰酶抑制剂，该抑制剂表现出混合酶抑制作用，并导致原代小鼠神经元培养物中乙酰化水平增加。通过筛选基于羟醛的 B/C/P 策略产生的大环内酰胺的所有 16 种立体异构体，使立体结构/活性关系 (SSAR) 的开发成为可能。
An aldol-based ‘build/couple/pair’ (B/C/P) strategy was applied to generate a collection of stereochemically and skeletally diverse small molecules. In the build phase, a series of asymmetric syn- and anti- aldol reactions were performed to produce four stereoisomers of a Boc protected γ-amino acid. In addition both stereoisomers of O-PMB-protected alaninol were generated to provide a chiral amine coupling partner. In the couple step, eight stereoisomeric amides were synthesized by coupling the chiral acid and amine building blocks. The amides were subsequently reduced to generate the corresponding secondary amines. In the pair phase, three different reactions were employed to enable intramolecular ring-forming processes, namely: nucleophilic aromatic substitution (SNAr), Huisgen [3+2] cycloaddition and ring-closing metathesis (RCM). Despite some stereochemical dependencies, the ring-forming reactions were optimized to proceed with good to excellent yields providing a variety of skeletons ranging in size from 8- to 14-membered rings. Scaffolds resulting from the RCM pairing reaction were diversified on solid-phase to yield a 14,400-membered library of macrolactams. Screening of this library led to the discovery of a novel class of histone deacetylase inhibitors, which display mixed enzyme inhibition and led to increased levels of acetylation in a primary mouse neuron culture. The development of stereo-structure/activity relationships (SSAR) was made possible by screening all 16 stereoisomers of the macrolactams produced through the aldol-based B/C/P strategy.
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影响因子：
7.8
作者：
Bauer, Renato A.;Wurst, Jacqueline M.;Tan, Derek S.
通讯作者：
Tan, Derek S.
影响因子：
14.8
作者：
Bradner, James E.;West, Nathan;Grachan, Melissa L.;Greenberg, Edward F.;Haggarty, Stephen J.;Warnow, Tandy;Mazitschek, Ralph
通讯作者：
Mazitschek, Ralph
影响因子：
15
作者：
FERGUSON, DM;RABER, DJ
通讯作者：
RABER, DJ
影响因子：
15
作者：
Boren, Brant C.;Narayan, Sridhar;Fokin, Valery V.
通讯作者：
Fokin, Valery V.
影响因子：
2.1
作者：
Amedio, JC;Bernard, PJ;Van Wagenen, G
通讯作者：
Van Wagenen, G