Aqueous Metathesis Catalysts for Biological Application

描述(申请人提供)：这项研究的目的是开发在质子化介质中起作用的烯烃歧化催化剂，并探索它们在生物学上的应用。早期的工作开发了在有机介质中起作用的催化剂，产生了类型为L2X2Ru=Chr的复分解活性络合物家族。大量的工作已经证明了这些络合物在有机介质中建立碳-碳双键的显着效用。然而，由于溶解度的限制，生物分子如多肽的修饰通常必须在质子性介质--通常是水中进行。烯烃在水中的化合反应将允许在温和的条件下进行转化，并在与生物分子中通常存在的官能团垂直的官能团上进行转化。 这项研究的目的之一是开发在质子溶剂中表现出足够的稳定性和活性，并能在生物相关的条件下发挥作用的L2X2Ru=Chr配合物。为此，L2X2Ru=Chr络合物的L类型的配体将被修饰，以包括已知的增加化合物在质子介质中的溶解度的基团--例如，聚乙二醇和/或季铵盐。还将探索使用螯合配体，因为它们已被证明可以提高复分解催化剂的稳定性。这种催化剂有可能成为探索和操纵与生物学有关的结构的有力工具。 鉴于这种催化剂的成功开发，本研究的第二个目标是证明烯烃复分解作为一种生物分子结构操纵工具的力量。提出了探索该催化剂对蛋白质进行定点翻译后修饰、生成聚合脂质体和构建新型可逆水凝胶的能力的项目。 开发的催化剂将根据特定应用的要求提供给面向生物的团体。仅在加州理工学院，Dervan、Dougherty和Tirrell团队就有项目可以立即使用建议的催化剂，目前的催化剂在有机介质中的广泛使用表明，随着建议催化剂的可用，复分解作用将出现新的生物应用。

DESCRIPTION (provided by applicant): The objective of this research is the development of olefin metathesis catalysts that function in protic media and the exploration of their biologically relevant applications. Earlier work developed catalysts that function in organic media yielding a metathesis-active family of complexes of the type L2X2Ru=CHR. A large body of work has demonstrated the remarkable utility of these complexes to build carbon-carbon double bonds in organic media. However, due to solubility constraints, the modification of biomolecules such as polypeptides often must be performed in protic media--typically water. Olefin metathesis in water will allow for transformations that proceed under mild conditions and operate on a functional group orthogonal to functionalities normally present in biomolecules. One aim of the proposed research is to develop L2X2Ru=CHR complexes that demonstrate sufficient stability and activity in protic solvents and which can function in biologically relevant conditions. To this end, the L-type ligands of the L2X2Ru=CHR complexes will be modified to include groups known to increase the solubility of a compound in protic media--e.g, poly(ethylene glycol) and/or quaternary ammonium salts. The use of chelating ligands will also be explored because they have been shown to increase the stability of metathesis catalysts. This catalyst has the potential to be a powerful tool in the exploration and manipulation of structures pertinent to biology. In anticipation of the successful development of this catalyst, the second goal of this research is the demonstration of the power of olefin metathesis as a tool for structural manipulation of biomolecules. Projects exploring the ability of the catalyst to site-specifically post-translationally modify proteins, generate polymerized liposomes, and construct novel reversible hydrogels are proposed. The developed catalysts will be provided to biologically-oriented groups as requested for specific applications. At Caltech alone, the Dervan, Dougherty, and Tirrell groups have projects where the proposed catalysts could be used immediately, and the broad use of the current catalysts in organic media suggests that novel biological applications of metathesis will arise with the availability of the proposed catalyst.