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

天然产品及其类似物和其他特殊结构基元对科学界的许多成员，特别是制药和农业化学工业部门的成员具有特殊的重要性。这些高价值实体中的大部分在其框架内并入含氮亚结构。关于天然产物，涉及其生物合成的两个重要的酶类是单胺氧化酶和亚胺还原酶。前者催化底物胺的氧化以产生高能亚胺中间体，而后者催化亚胺的还原以形成对映体纯的手性胺。Turner和Whitehead小组先前的合作研究已经证明了这两种酶单独和串联用于制备工业相关结构如手性3-取代哌啶和官能化苄基胺的应用。规模合成工作成功制备了抗糖尿病药物Preclamol的类似物，这是一种抗肿瘤药物WP 1066的生物学有效类似物，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（i）开发和扩展工程化单胺氧化酶和亚胺还原酶的可用“工具箱”，以及（ii）开发用于制备这些生物催化剂的特定底物的有效制备合成方法-这将最终导致新颖的化学-酶促路线，以获得特权结构构建块以及生物活性天然和非天然产物。该学科项目将为博士生提供先进的有机合成，生物催化剂开发和先进的质谱相结合的领域的“国家的最先进的”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/亚胺鎓离子生物催化剂作为高效制备规模化学反应的通用催化剂的广泛且迄今为止尚未开发的潜力;- 它将为合成，医药和生物化学领域的研究人员提供获得特权结构基序的有效途径，多功能合成积木和天然产物类支架，否则将很难或不可能获得。这些影响清楚地表明，该项目牢牢地坐在工业生物技术的BBSRC主题。此外，监督小组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.