Synthesis of Libraries of Statine Analogues

他汀类似物文库的合成

• 批准号: 6691416
• 负责人: SPIROS KAMBOURAKIS
• 金额: $ 10万
• 依托单位: BIOCATALYTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6691416
• 关键词: aminoalcohol; analog; chemical registry /resource; chemical synthesis; enzyme substrate; method development; molecular cloning; oxidoreductase; stereochemistry; stereoisomer

DESCRIPTION (provided by applicant): Statine and its analogs represent a key class of intermediates for drug spanning a wide range of indications. Presently, only two of these compounds, statine and phenylstatine, are commercially available, and of the four possible diastereomers, only the (3S,4S) and (3R,4S) forms are offered. Furthermore, current prices of more than $1000 per gram are so high that incorporation of these important intermediates into developmental drug candidates is inhibited. In this Phase 1 proposal we seek to establish a simple two-step chemo-enzymatic method for the synthesis of a library of statine analogues in all possible diastereomeric forms. In the first step, homologation of alpha-amino acids into the corresponding beta-keto statine analogues will be achieved using chemical methodology that has been well-established in our laboratory. Stereoselective reduction of the ketone using ketoreductase enzymes is the second step. Ten or more broad range ketoreductases that have been cloned, over-expressed, and produced in our laboratories will be screened for activity against at least ten different beta-keto statine analogues, and the feasibility of the method will be proven by producing at least three different statine analogs at the gram scale. This method, if successful, will make a wide range of statine analogues readily available at significantly lower cost.

描述（由申请人提供）：他汀及其类似物代表了一类关键的药物中间体，涵盖多种适应症。目前，这些化合物中只有两种，他汀和苯他汀，是可商购的，并且在四种可能的非对映异构体中，仅提供(3S,4S)和(3R,4S)形式。此外，目前每克超过 1000 美元的价格如此之高，以至于无法将这些重要的中间体纳入开发候选药物中。在这一第一阶段提案中，我们寻求建立一种简单的两步化学酶方法，用于合成所有可能的非对映体形式的他汀类似物库。第一步，将使用我们实验室成熟的化学方法将α-氨基酸同系为相应的β-酮他汀类似物。使用酮还原酶立体选择性还原酮是第二步。我们的实验室将筛选十种或更多种已克隆、过表达和生产的广泛酮还原酶，以确定其针对至少十种不同的β-酮他汀类似物的活性，并且将通过在克规模生产至少三种不同的他汀类似物来证明该方法的可行性。这种方法如果成功，将使多种他汀类似物以显着更低的成本变得容易获得。