Discovery, development and application of novel amine and imine biocatalysts for the synthesis of natural products, their analogues and other privileg

天然产物、它们的类似物和其他特殊的结构基序对科学界的许多成员，特别是制药和农用化学工业部门的成员来说，具有特别重要的意义。这些高价值实体中有很大一部分在其框架内包含含氮的子结构。就天然产物而言，参与其生物发生的两类重要酶是单胺氧化酶和亚胺还原酶。前者催化底物胺氧化生成高能亚胺中间体，后者催化亚胺还原生成对映体纯手性胺。Turner和Whitehead团队之前的合作研究已经证明了这两类酶的应用，无论是单独的还是串联的，都可以用于制备工业上相关的结构，如手性3-取代哌啶和功能化苄胺。制备规模的合成工作已经成功地制备了抗糖尿病药物Preclamol的类似物，这是一种抗肿瘤药物WP1066的生物有效类似物，也是合成抗癌药物Niraparib的关键中间体。这个跨学科项目的目标是：(1)开发和扩展工程单胺氧化酶和亚胺还原酶的可用“工具箱”；(2)为这些生物催化剂的特定底物的制备开发有效的制备合成方法——这将最终导致新的化学酶途径，以获得特殊的结构构建块以及生物活性的天然和非天然产品。这是一个多学科项目，将为博士生提供先进有机合成、生物催化剂开发和先进质谱分析等领域的“最先进”培训。在更广泛的背景下，该项目的成功结果将在两个方面产生广泛的影响：-它将展示胺和亚胺/亚胺离子生物催化剂作为高效制备规模化学反应的多功能催化剂的广泛和迄今为止尚未开发的潜力；-它将为合成、药物和生物化学领域的研究人员提供有效的途径，以获得特殊的结构基序、通用的合成构建模块和天然产品样支架，否则这些将很难或不可能获得。这些影响清楚地表明，该项目完全符合BBSRC的工业生物技术主题。此外，监督团队的三名成员的协同科学专业知识预计将导致开发新的有效方法来发现，优化和应用新的生物催化剂，这对工业和学术研究界都非常重要。

Natural products, their analogues and other privileged structural motifs are of exceptional importance to many members of the scientific community, particularly those in the pharmaceutical and agrochemical industrial sectors. A large percentage of these high value entities incorporate nitrogen-containing substructures within their frameworks. With respect to natural products, two important enzyme classes, which are involved in their biogenesis, are the monoamine oxidases and imine reductases. The former of these catalyse the oxidation of substrate amines to generate high energy, imine intermediates whereas the latter catalyse the reduction of imines to form enantiomerically pure chiral amines. Previous collaborative research by the Turner and Whitehead groups has demonstrated application of the two enzyme classes, both individually and in tandem, for the preparation of industrially relevant structures such as chiral 3-substituted piperidines and functionalised benzylic amines. Preparative scale synthetic work has resulted in the successful preparation of analogues of the anti-diabetes drug Preclamol, a biologically potent analogue of the anti-tumour drug WP1066, and a key intermediate in the synthesis of the anti-cancer agent Niraparib. The goal of this cross-disciplinary project is to (i) develop and expand the available "toolbox" of engineered monoamine oxidases and imine reductases and (ii) develop efficient preparative synthetic approaches for the preparation of specific substrates for these biocatalysts - this will ultimately lead to novel chemo-enzymatic routes to privileged structural building blocks as well as bio-active natural and unnatural products.This is a multi-disciplinary project which will provide a PhD student with 'state-of-the-art' training in the combined fields of advanced organic synthesis, biocatalyst development and advanced mass spectrometry. In a broader context, a successful outcome to the project will have widespread impact on two fronts:- it will demonstrate the extensive and, so far, mostly untapped potential of amine and imine/iminium ion biocatalysts as versatile catalysts for efficient preparative scale chemical reactions;- it will provide researchers in the synthetic, medicinal and biological chemistry fields with efficient routes to privileged structural motifs, versatile synthetic building blocks and natural product-like scaffolds which would otherwise be difficult, or impossible, to obtain.These impacts clearly demonstrate that the project sits firmly within the BBSRC theme of Industrial Biotechnology. Furthermore, the synergistic scientific expertise of the three members of the supervisory team is expected to result in the development of novel and effective approaches to the discovery, optimisation and application of new biocatalysts which are of great importance to both industrial and academic research communities.