Selective P450 Oxidation Catalysts for Synthesis of Bioactive Molecules

描述(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。开发出能够提供这种转化的有效方法，特别是在具有生物活性的天然产品的背景下，必然会揭示这些分子转化中前所未有的机会，从而加速药物发现工作。在这一应用中，我们提出了旨在开发强有力的新方法来利用P450C-H氧化催化和P450介导的合成来选择性转化复杂天然产物中的非活性脂肪族C-H键的研究。为此，将实施有效和及时有效的策略，以实现底物反应性的定制、P450单加氧酶的区域立体选择性和快速生成选择性P450催化剂，以调节复杂有机支架中不同的未活化脂肪族中心的功能化。在所提出的策略的基础上，有了一种新的使能方法来绘制P450单加氧酶的活性位点配置图，并快速获得这些酶的丰富信息的功能图谱(‘P450指纹’)。将采用系统的方法通过分析P450变异体的指纹来预测其反应活性，并确定在不破坏催化功能的情况下改变P450单加氧酶活性部位配置的最佳诱变方案。这些新工具将被应用于获得具有特制的区域和立体选择性的P450催化剂，用于具有临床相关的抗癌和抗疟疾活性的萜烯中多个脂肪族位置的羟基化。这些努力将为这些分子的后期转化开辟新的途径，以改善它们的药理特性。通过将P450催化的选择性脂肪族羟基化与化学合成偶联，这些天然产物的新的和目前无法获得的衍生物将可用于活性评估。通过这些研究，将全面了解这些天然产物的结构和活性，为开发更有效的抗白血病和抗疟疾药物提供基础。完成这项申请的主要目标将导致一套强大的通用战略的P450碳-氢氧化催化剂 开发，这将很容易适用于各种其他天然产品和高价值化合物。

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.