Natural feedstocks for diversity oriented synthesis

描述（由申请人提供）：此STTR申请要求资金支持将特定合成专业知识和方法从达特茅斯学院的Wright Group转移到Promiliad Bioburma的研究人员，以努力将Promiliad的REBACS策略降低到实践水平。这些努力将集中在使用一个高复杂性的原料，九乳酸，作为出发点的多样性导向的合成。将在Promiliad通过涉及发酵、重组生物化学和化学技术的工艺生产非外消旋（+）和（-）九乳酸。这些化合物的补充量将提供给赖特集团，用于转化为特定的化合物，这些化合物将作为新的药物线索在Promiliad进行检查。主要的焦点将涉及到合成一类新的大环内酯称为nonactolides。设计这些化合物的明确目的是模拟细菌核糖体中大环内酯类抗生素的结构，以鉴定靶向细菌核糖体的新的先导抗生素。第一代化合物将由达特茅斯的工人制备，并提供给Promiliad进行测试。第二，平行的努力，将集中在转化的nonacetic酸一类新的β-turn模拟物称为酮氨基酸。这些化合物被设计为模拟生物活性肽的特定结构特征，用于基于肽模拟的药物发现。这些化合物将类似于目前使用的糖氨基酸，但在成本效益和合成灵活性方面提供了特定的优势。该提案的最后一项倡议是开发化学方法来扩大九乳酸中固有的多样性。这些基础研究将集中在将额外的反应功能位点纳入天然支架的方法上。将这些多样性扩展的构建模块集成到先前讨论的设计中将大大增加我们将能够在我们的铅发现计划中使用的化合物的多样性和量值。

DESCRIPTION (provided by applicant): This STTR application requests funds to support the transfer of specific synthetic expertise and methodologies from the Wright Group at Dartmouth College to investigators at Promiliad Biopharma in an effort to reduce Promiliad's REBACS strategy to the level of practice. These efforts will focus on the use of a high-complexity feedstock, nonactic acid, as the point of departure for diversity oriented synthesis. Nonracemic (+) and (-) nonactic acid will be produced at Promiliad through a process involving fermentation, recombinant biochemical and chemical technologies. Preparative amounts of these compounds will be provided to the Wright group for conversion to specific compounds that will be examined as new pharmaceutical leads at Promiliad. The main focus will relate to the synthesis of a new class of macrolides known as the nonactolides. These compound have been designed with the express purpose of mimicing the structure of the macrolide antibiotics in an attemp to identify new lead antibiotics that target the bacterial ribosome. First generation compounds will be prepared by the Dartmouth workers and provided to Promiliad for testing. A second, parallel effort, will focus on the conversion of nonactic acid to a new class of beta-turn mimetics known as ketide amino acids. These compounds are designed to mimic specific structural features common to bioactive peptides for use in peptidomimetic-based drug discovery. These compound will be similar to the currently employed sugar amino acids but offer specific advantages in cost effectiveness and synthetic flexibility. The final initiative in this proposal is to develop chemical methodoogies to amplify the diversity inherently present in nonactic acids. These basic studies will focus on methods to incorporate additional sites of reactive functionality into the natural scaffold. Integration of these diversity-expanded building blocks into the previously discussed designs will greatly increase the diversity and magnituted of the compound we will be able to use in our lead discovery program.