Concise Chemoenzymatic Total Synthesis and Identification of Cellular Targets of Cepafungin I.
Concise Chemoenzymatic Total Synthesis and Identification of Cellular Targets of Cepafungin I.
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DOI：
10.26434/chemrxiv.11852496.v1
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发表时间：
2020-02
影响因子：
8.6
通讯作者：
A. Amatuni;A. Shuster;A. Adibekian;Hans Renata
中科院分区：
文献类型：
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作者：
A. Amatuni;A. Shuster;A. Adibekian;Hans Renata
天然产物头孢芬净I最近通过一系列体外活性测定被报道是20 S蛋白酶体核心颗粒的最有效的共价抑制剂之一。在这里，我们报告了一个简短的化学酶全合成头孢芬净我具有使用的区域选择性酶促氧化，以制备一个关键的羟基化的氨基酸积木在一个可扩展的方式。本文开发的策略使得能够获得化学蛋白质组学探针，这反过来揭示了头孢芬净I对蛋白酶体的β2和β5亚基的特殊选择性和效力。进一步的结构-活性关系研究表明大环中羟基的关键作用和脂质尾在调节该天然产物家族的效力中的身份。本研究为进一步的药物化学探索奠定了基础，以充分发挥头孢芬净I的抗癌潜力。
The natural product cepafungin I was recently reported to be one of the most potent covalent inhibitors of the 20S proteasome core particle through a series of in vitro activity assays. Here, we report a short chemoenzymatic total synthesis of cepafungin I featuring the use of a regioselective enzymatic oxidation to prepare a key hydroxylated amino acid building block in a scalable fashion. The strategy developed herein enabled access to a chemoproteomic probe, which in turn revealed the exceptional selectivity and potency of cepafungin I toward the β2 and β5 subunits of the proteasome. Further structure-activity relationship studies suggest the key role of the hydroxyl group in the macrocycle and the identity of the lipid tail in modulating the potency of this natural product family. This study lays the groundwork for further medicinal chemistry exploration to fully realize the anticancer potential of cepafungin I.