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Selective Synthesis of the Human Drug Metabolite 5′-Hydroxypropranolol by an Evolved Self-Sufficient Peroxygenase
ACS Catalysis ( IF 12.9 ) Pub Date : 2018-04-19 00:00:00 , DOI: 10.1021/acscatal.8b01004
Patricia Gomez de Santos 1 , Marina Cañellas 2 , Florian Tieves 3 , Sabry H. H. Younes 3 , Patricia Molina-Espeja 1 , Martin Hofrichter 4 , Frank Hollmann 3 , Victor Guallar 2 , Miguel Alcalde 1
Affiliation  

Propranolol is a widely used beta-blocker that is metabolized by human liver P450 monooxygenases into equipotent hydroxylated human drug metabolites (HDMs). It is paramount for the pharmaceutical industry to evaluate the toxicity and activity of these metabolites, but unfortunately, their synthesis has hitherto involved the use of severe conditions, with poor reaction yields and unwanted byproducts. Unspecific peroxygenases (UPOs) catalyze the selective oxyfunctionalization of C–H bonds, and they are of particular interest in synthetic organic chemistry. Here, we describe the engineering of UPO from Agrocybe aegerita for the efficient synthesis of 5′-hydroxypropranolol (5′-OHP). We employed a structure-guided evolution approach combined with computational analysis, with the aim of avoiding unwanted phenoxyl radical coupling without having to dope the reaction with radical scavengers. The evolved biocatalyst showed a catalytic efficiency enhanced by 2 orders of magnitude and 99% regioselectivity for the synthesis of 5′-OHP. When the UPO mutant was combined with an H2O2 in situ generation system using methanol as sacrificial electron donor, total turnover numbers of up to 264 000 were achieved, offering a cost-effective and readily scalable method to rapidly prepare 5′-OHP.

中文翻译:

进化的自足过氧合酶的选择性合成人药物代谢产物5'-羟基普萘洛尔

普萘洛尔是一种广泛使用的β受体阻滞剂,可通过人肝P450单加氧酶代谢为等价的羟基化人药代谢物(HDM)。评估这些代谢物的毒性和活性对于制药业至关重要,但是不幸的是,迄今为止,它们的合成涉及使用苛刻的条件,不良的反应收率和有害的副产物。非特异性过氧化酶(UPOs)催化C–H键的选择性氧化官能化,在合成有机化学中特别重要。在这里,我们描述了Agrocybe aegerita的UPO工程用于有效合成5'-羟基普萘洛尔(5'-OHP)。我们采用了一种结构指导的演化方法,并结合了计算分析,目的是避免不必要的苯氧基自由基偶联,而不必用自由基清除剂对反应进行掺杂。进化的生物催化剂显示出对于5'-OHP的合成,催化效率提高了2个数量级和99%的区域选择性。当UPO突变体与使用甲醇作为牺牲电子供体的H 2 O 2原位生成系统结合使用时,总营业额高达264 000,这为快速制备5'-OHP提供了一种经济高效且易于扩展的方法。
更新日期:2018-04-19
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