Chemoselective Wittig and Michael ligations of unprotected peptidyl phosphoranes in water furnish potent inhibitors of caspase-3.
Chemoselective Wittig and Michael ligations of unprotected peptidyl phosphoranes in water furnish potent inhibitors of caspase-3.
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DOI：
10.1021/ol501910x
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发表时间：
2014-08
期刊：
影响因子：
5.2
通讯作者：
K. Holland‐Nell;M. I. Fernández-Bachiller;Ahsanullah;J. Rademann
中科院分区：
文献类型：
--
作者：
K. Holland‐Nell;M. I. Fernández-Bachiller;Ahsanullah;J. Rademann
具有 Ac-L-天冬氨酰-L-谷氨酰-L-缬氨酰-L-天冬氨酰序列的未保护肽基正膦 1 从聚合物载体上释放出来，并在维蒂希连接中在水性介质中与脂肪族和芳香族醛反应。获得的乙烯基酮 6-12 是 caspase-3 的有效抑制剂。衍生自甲醛的乙烯基酮 6 与硫醇亲核试剂发生迈克尔连接，提供产物 14-16，也在水介质中进行。所证明的连接反应能够在水中修饰复杂的功能化肽，从而提供无侧链保护的生物活性蛋白质配体。
Unprotected peptidyl phosphoranes 1 with sequence Ac-L-aspartyl-L-glutamyl-L-valinyl-L-aspartyl are released from polymer support and react with aliphatic and aromatic aldehydes in aqueous medium in a Wittig ligation. Obtained vinyl ketones 6-12 are potent inhibitors of caspase-3. Vinyl ketone 6, derived from formaldehyde, undergoes Michael ligations with thiol nucleophiles furnishing products 14-16, also in aqueous medium. The demonstrated ligation reactions enable the modification of complex functionalized peptides in water providing bioactive protein ligands without side-chain protection.