STTR Phase I: Enzymatic Synthesis of Chiral Cyclopropanes for Pharmaceutical Drug Synthesis and Agricultural Crop Protection Applications

STTR 第一阶段：用于药物合成和农作物保护应用的手性环丙烷的酶法合成

• 批准号: 1549855
• 负责人: David Rozzell
• 金额: $ 22.5万
• 依托单位: Provivi Inc.
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1549855&HistoricalAwards=false
• 关键词: STTR; Phase; Enzymatic; Synthesis; Chiral

The broader impact/commercial potential of this Small Business Innovation Research Phase I project is to develop novel, breakthrough enzyme-catalyzed reactions that can be applied to the production of pharmaceuticals and crop protection agents. By establishing a broadly applicable biocatalytic alternative to produce an important class of compounds called chiral cyclopropanes, Provivi will create safer, cleaner, and lower cost synthetic routes. In most cases the application of this new biocatalytic reaction will reduce the number of steps and lower the required capital investment for the synthesis of these key building blocks. The new enzyme technology being developed in this research will improve the synthesis of both existing drugs and compounds in current drug development pipelines. Further applications are envisioned in the production of new crop protection agents. The enzymes being developed have the advantage of being optimizable for each specific target product using modern molecular biology methods. Furthermore, performing the reactions in aqueous conditions will reduce the need for organic solvents, improving the sustainablility of the processes. Replacing existing chemical routes with the more efficient and sustainable enzyme-catalyzed steps will reduce the cost and improve the purity of many advanced pharmaceutical intermediates used in drug synthesis.The technical objectives of this Phase I research project are to demonstrate the application of the novel enzymatic cyclopropanation reaction to the production of a variety of commercial drug substances. Chiral cyclopropanes are key substructures found in a number of pharmaceutical and crop protection compounds. The cyclopropane-containing building blocks used in the synthesis of these compounds contain at least one, and often more than one, chiral center. Since biological activity typically requires having a single stereoisomer, chemical methods that achieve high stereoselectivity are continually sought. For cyclopropanation reactions, the existing methods typically rely on transition-metal catalysts such as rhodium bearing chiral ligands. The biocatalytic method offers clear advantages over the contemporary chemistry in that it will circumvent the use of rare, expensive metals and costly auxiliary ligands for these types of reactions. High temperatures and harsh conditions will also be avoided. In this research, high-throughput screening will be used to identify improved variants that catalyze desired cyclopropanation reactions at greater rates and with increased stereoselectivity. By developing an expanded set of cyclopropanation biocatalysts with capabilities to act on a wider range of starting materials, the scope and utility of this novel enzymatic reaction will be increased.

这个小企业创新研究第一阶段项目的更广泛的影响/商业潜力是开发新的，突破性的酶催化反应，可应用于药品和作物保护剂的生产。通过建立一种广泛适用的生物催化替代品来生产一类重要的化合物，称为手性环丙烷，Provivi将创造更安全，更清洁，成本更低的合成路线。在大多数情况下，这种新的生物催化反应的应用将减少步骤的数量，并降低合成这些关键构件所需的资本投资。这项研究中开发的新酶技术将改善现有药物和化合物在当前药物开发管道中的合成。 在新的作物保护剂的生产中设想了进一步的应用。正在开发的酶具有使用现代分子生物学方法针对每个特定目标产物进行优化的优点。此外，在水性条件下进行反应将减少对有机溶剂的需求，从而提高工艺的可持续性。用更高效和可持续的酶催化步骤取代现有的化学路线将降低药物合成中使用的许多高级药物中间体的成本并提高其纯度。该I期研究项目的技术目标是展示新型酶促环丙烷化反应在多种商业原料药生产中的应用。手性环丙烷是在许多药物和作物保护化合物中发现的关键亚结构。在这些化合物的合成中使用的含环丙烷的结构单元含有至少一个，并且通常多于一个手性中心。由于生物活性通常需要具有单一立体异构体，因此不断寻求实现高立体选择性的化学方法。对于环丙烷化反应，现有的方法通常依赖于过渡金属催化剂，例如带有手性配体的铑。生物催化方法相对于当代化学具有明显的优势，因为它将避免使用稀有，昂贵的金属和昂贵的辅助配体进行这些类型的反应。高温和恶劣的条件也将被避免。在这项研究中，高通量筛选将被用来确定改进的变体，催化所需的环丙烷化反应在更大的速度和增加的立体选择性。通过开发一套扩大的环丙烷化生物催化剂，其能够作用于更广泛的起始材料，将增加这种新型酶促反应的范围和实用性。