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碳氢键的选择性功能化仍然是有机化学中最具挑战性的问题。开发有效的方法来进行这种转化，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，从而加速药物发现的努力。在这个应用中，我们建议研究旨在开发强大的新方法来利用P450 C-H氧化催化和P450介导的合成来选择性转化复杂天然产物中的非反应性脂肪族C-H键。为此，将实施高效和时效的策略，以定制底物反应性，P450单加氧酶的区域和立体选择性，并快速生成选择性P450催化剂，以介导复杂有机支架中不同非活化脂肪脂肪位点的功能化。在提出的策略的基础上，有一种新的使能方法来绘制P450单加氧酶的活性位点结构，并快速获取这些酶的信息丰富的功能谱（“P450指纹”）。系统的方法将通过分析P450变异的指纹来预测其反应性，并确定在不破坏催化功能的情况下改变P450单加氧酶活性位点结构的最佳诱变方案。这些新工具将用于获得具有定制区域和立体选择性的P450催化剂，用于萜烯中多个脂肪体位置的羟基化，具有临床相关的抗癌和抗疟疾活性。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。通过将选择性p450催化的脂肪羟基化偶联到化学合成中，这些天然产物的新颖且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。本应用的主要目标的完成将为P450 C-H氧化催化剂的研究提供一套强大而通用的策略

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.