Synthesis of Homochiral beta-Branched-Chain Amino Acids

同手性 β-支链氨基酸的合成

• 批准号: 6834239
• 负责人: JAMES L KILGORE
• 金额: $ 10万
• 依托单位: BIOCATALYTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6834239
• 关键词: alkylation; aminoacid analog; anions; chemical synthesis; conformation; drug design /synthesis /production; drug discovery /isolation; enzyme mechanism; gene expression; glycine; hydrolase; oxidoreductase; peptides; polymerase chain reaction; stereochemistry; stereoisomer

DESCRIPTION (provided by applicant): Many nonproteogenic amino acids have proved useful for inhibiting biodegradation and improving biological activity in peptides and peptidomimetic drugs. Few non-genetically encoded branched-chain amino acids (BCAAs) are commercially available, despite the importance of BCAA side-chain interactions in determining polypeptide structure. Chiral branches permit fine-tuning of biological activity by subtly changing side-chain shapes. For example, D-isoleucine substitution gives more specific and effective insulin and vasopressin antagonists, and potent short antiangiogenic peptides. Branch-carbon configurations of beta-methyl arylamino acids strongly affect activity. Thus beta-chiral BCAAs can provide better models for bioactive polypeptide conformations and greatly improve both activity and duration of action in peptide therapeutics. Most syntheses of beta-chiral BCAAs begin by stereorandomly building carbon skeletons, then separating diastereomers and finally enantiomers. In the case of D-alloisoleucine, numerous attempts to improve on this inefficient synthetic strategy have only resulted in expensive, complex processes which are difficult to scale up. Interest in less-common branched-chain amino acids is high, but commercial sources are currently not providing the quantities needed for drug development at acceptable cost. In developing a scalable enzymatic process to cleanly isomerize L-Ile to D-allo-Ile, we realized that obtaining amino acid frameworks with the correct side-chain branch configuration is the crucial problem in making any beta-branched BCAA, because stereo directed epimerizations can quantitatively convert alpha-isomeric mixtures to homochiral )roducts. We will compare the synthetic and economic merits of straightforward glycine anion alkylations with two novel cyclopropane ring-opening procedures for making amino acids with beta-chiral branches. alpha-Carbon epimers will then be made uniformly D- or L- by well-precedented chemoenzymatic processes.

描述（由申请人提供）：许多非蛋白质氨基酸已被证明可用于抑制肽和拟肽药物的生物降解和提高生物活性。尽管支链氨基酸侧链相互作用在决定多肽结构中的重要性，但很少有非遗传编码的支链氨基酸（BCAA）可商购获得。手性分支允许通过微妙地改变侧链形状来微调生物活性。例如，D-异亮氨酸取代产生更特异和有效的胰岛素和加压素拮抗剂，以及有效的短抗血管生成肽。β-甲基芳基氨基酸的支链碳构型强烈影响活性。因此，β-手性支链氨基酸可以为生物活性多肽构象提供更好的模型，并大大改善肽治疗剂的活性和作用持续时间。 大多数β-手性支链氨基酸的合成开始通过立体随机地构建碳骨架，然后分离非对映体，最后分离对映体。在D-别异亮氨酸的情况下，改进这种低效合成策略的许多尝试只导致昂贵、复杂的方法，难以扩大规模。对不太常见的支链氨基酸的兴趣很高，但商业来源目前无法以可接受的成本提供药物开发所需的数量。在开发将L-Ile干净地异构化为D-allo-Ile的可扩展的酶促方法中，我们认识到获得具有正确侧链分支构型的氨基酸框架是制备任何β-分支BCAA的关键问题，因为立体定向差向异构化可以定量地将α-异构体混合物转化为纯手性产物。我们将比较直接的甘氨酸阴离子烷基化与两种新的环丙烷开环程序，使氨基酸与β-手性分支的合成和经济的优点。然后通过已有的化学酶法将α-碳差向异构体均匀地制成D-或L-。