Selective P450 Oxidation Catalysts for Synthesis of Bioactive Molecules

描述（由申请人提供）：复杂有机分子中脂肪族C-H键的选择性官能化仍然是有机化学中最具挑战性的问题。开发提供这种转化的有效方法，特别是在生物活性天然产物的背景下，必然会在这些分子的转化中揭示前所未有的机会，从而加速药物发现工作。在此应用中，我们提出了旨在开发强大的新方法来利用P450 C-H氧化催化和P450介导的合成，以选择性转化复杂天然产物中的非反应性脂肪族C-H键的研究。为此，将实施有效和时间有效的策略，以使得能够定制底物反应性、P450单加氧酶的区域立体选择性和快速产生选择性P450催化剂，用于介导复杂有机支架内的不同未活化脂族位点的官能化。在所提出的策略的基础上，有一个新的使能方法来映射P450单加氧酶的活性位点配置，并迅速获得这些酶的信息丰富的功能概况（“P450指纹”）。将实施系统的方法来预测P450变体的反应性，通过分析它们的指纹，并确定最佳的诱变方案，用于改变P450单加氧酶中的活性位点构型，而不破坏催化功能。这些新的工具将被应用于获得P450催化剂，其具有定制的区域和立体选择性，用于具有临床相关抗癌和抗疟疾活性的萜烯中的多个aliphati位置的羟基化。这些努力将为这些分子的后期转化开辟新的途径，以改善其药理学特性。通过将选择性P450催化的脂肪族羟基化与化学合成相结合，这些天然产物的新的和目前难以获得的衍生物将可用于活性评价。通过这些研究，将收集这些天然产物的全面结构-活性见解，为开发更有效的抗白血病和抗疟疾药物提供基础。完成本申请的主要目标将导致一套强大的和通用的策略P450 C-H氧化催化剂 这将很容易适用于各种其他天然产品和高价值化合物的开发。

DESCRIPTION (provided by applicant): The selective functionalization of aliphatic C-H bonds in complex organic molecules remains a most challenging problem in organic chemistry. Development of efficient methods to afford this transformation, in particular in the context of biologically active natural products, is bound to disclose unprecedented opportunities in the transformation of these molecules, thereby accelerating drug discovery efforts. In this application, we propose research aimed at developing powerful new methodologies to exploit P450 C-H oxidation catalysis and P450-mediated synthesis for selective transformation of unreactive aliphatic C-H bonds in complex natural products. To this end, efficient and time-effective strategies will be implemented to enable tailoring of the substrate reactivity, regio- an stereoselectivity of P450 monooxygenases and rapid generation of selective P450 catalysts for mediating functionalization of distinct unactivated aliphatic sites within a complex organic scaffold. At the basis of the proposed strategies there is a new enabling methodology to map the active site configuration in P450 monooxygenases and rapidly acquire information-rich functional profiles of these enzymes ('P450 fingerprints'). Systematic methods will be implemented to predict the reactivity of P450 variants via analysis of their fingerprints and to identify optimal mutagenesis schemes for altering the active site configuration in P450 monooxygenases without disrupting catalytic function. These new tools will be applied to obtain P450 catalysts with tailor-made regio- and stereoselectivity for hydroxylation of multiple aliphati positions in terpenes with clinically relevant anticancer and antimalarial activity. These efforts will unlock new avenues for late-stage transformation of these molecules in order to improve their pharmacological properties. By coupling selective P450-catalyzed aliphatic hydroxylations to chemical synthesis, novel and currently inaccessible derivatives of these natural products will be made available for activity evaluation. Through these studies, comprehensive structure-activity insights will be gleaned on these natural products, providing a basis for development of more potent antileukemic and antimalarial agents. Completion of the primary objectives of this application will result in a set of powerful and general strategies for P450 C-H oxidation catalyst development which will be readily applicable to a variety of other natural products and high- value compounds.