Natural feedstocks for diversity oriented synthesis

描述(由申请人提供)：这项申请申请资金，以支持从达特茅斯学院的莱特小组向Promiliad Biophma的研究人员转让特定的合成专业知识和方法，以努力将Promiliad的REBACS战略降低到实践水平。这些努力将集中在使用一种高度复杂的原料--非乳酸，作为面向多样性合成的起点。Promiliad将通过发酵、重组生化和化学技术生产非外消旋(+)和(-)非乳酸。这些化合物的制备量将被提供给莱特集团，用于转化为特定的化合物，这些化合物将作为Promiliad的新药物线索进行审查。主要的焦点将与合成一类新的大环内酯类化合物有关，这些大环内酯类化合物被称为非乳内酯。这些化合物的设计目的是模仿大环内酯类抗生素的结构，试图寻找针对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公司的工人准备并提供给Promiliad进行测试。第二项平行的努力将专注于将非乳酸转化为一种新的β-转折模拟物，称为酮类氨基酸。这些化合物旨在模仿生物活性多肽共同的特定结构特征，用于基于多肽的药物发现。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具有独特的优势。这项提案的最后一项倡议是发展化学方法学，以扩大非乳酸固有的多样性。这些基础研究将重点放在将更多的反应性功能结合到天然支架中的方法上。将这些多样性扩展的构建块整合到前面讨论的设计中，将极大地增加我们将能够在Lead发现计划中使用的化合物的多样性和数量。

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.