Biocatalysis in Drug Design: Engineered Reductive Aminases (RedAms) Are Used to Access Chiral Building Blocks with Multiple Stereocenters.
Biocatalysis in Drug Design: Engineered Reductive Aminases (RedAms) Are Used to Access Chiral Building Blocks with Multiple Stereocenters.
复制标题
DOI：
10.1021/jacs.3c07010
复制
发表时间：
2023-10-11
影响因子：
15
通讯作者：
Turner, Nicholas J.
中科院分区：
文献类型：
--
作者：
Casamajo, Arnau Rue;Yu, Yuqi;Schnepel, Christian;Morrill, Charlotte;Barker, Rhys;Levy, Colin W.;Finnigan, James;Spelling, Victor;Westerlund, Kristina;Petchey, Mark;Sheppard, Robert J.;Lewis, Richard J.;Falcioni, Francesco;Hayes, Martin A.;Turner, Nicholas J.
通过构建结构-活性-特性-毒理学关系，在寻找创新的生物活性小分子治疗药物的过程中，不断需要新的构建模块。具有多个立体中心的复杂手性分子是化合物文库扩展的重要组成部分，但传统的有机合成方法难以获得。在此，我们报告了一种生物催化过程，以获得用于药物发现的手性胺构建块的特定非对映体。一个还原性氨酶（RedAm）被设计成一个结构导向的诱变策略，以产生所需的异构体。改造后的ream （IR-09 W204R）能够以45%的转化率和95%的ee从外消旋酮2中生成（S，S，S）-异构体3。随后钯催化的3脱烯化反应以73%的产率得到目标伯胺4。该工程生物催化剂已用于制备规模，并代表了进一步工程和工艺开发的潜在起点。
Novel building blocks are in constant demand during the search for innovative bioactive small molecule therapeutics by enabling the construction of structure–activity–property–toxicology relationships. Complex chiral molecules containing multiple stereocenters are an important component in compound library expansion but can be difficult to access by traditional organic synthesis. Herein, we report a biocatalytic process to access a specific diastereomer of a chiral amine building block used in drug discovery. A reductive aminase (RedAm) was engineered following a structure-guided mutagenesis strategy to produce the desired isomer. The engineered RedAm (IR-09 W204R) was able to generate the (S,S,S)-isomer 3 in 45% conversion and 95% ee from the racemic ketone 2. Subsequent palladium-catalyzed deallylation of 3 yielded the target primary amine 4 in a 73% yield. This engineered biocatalyst was used at preparative scale and represents a potential starting point for further engineering and process development.
登录
查看更多内容
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：
7.3
作者：
Brow, Dean G.;Bostrom, Jonas
通讯作者：
Bostrom, Jonas
影响因子：
8.4
作者：
Mangas-Sanchez J;Sharma M;Cosgrove SC;Ramsden JI;Marshall JR;Thorpe TW;Palmer RB;Grogan G;Turner NJ
通讯作者：
Turner NJ
影响因子：
8
作者：
France, Scott P;Lewis, Russell D;Martinez, Carlos A
通讯作者：
Martinez, Carlos A
影响因子：
15
作者：
Harawa, Vanessa;Thorpe, Thomas W.;Marshall, James R.;Sangster, Jack J.;Gilio, Amelia K.;Pirvu, Lucian;Heath, Rachel S.;Angelastro, Antonio;Finnigan, James D.;Charnock, Simon J.;Nafie, Jordan W.;Grogan, Gideon;Whitehead, Roger C.;Turner, Nicholas J.
通讯作者：
Turner, Nicholas J.