Enzymatic Fluoroalkylation using Te-Adenosyl-Telluromethionine Analogs and Late-Stage Diversification of Natural Products Exhibiting Antibacterial Behavior

使用Te-腺苷-碲甲硫氨酸类似物进行酶促氟烷基化以及表现出抗菌行为的天然产物的后期多样化

• 批准号: 10372230
• 负责人: SQUIRE J. BOOKER
• 金额: $ 15.75万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372230
• 关键词: 6-Mercaptopurine; Achievement; Acids; Affinity; Amino Acids; Anabolism; Anti-Bacterial Agents; Antibiotics; Behavior; Biological; Carbon; Catechol O-Methyltransferase; Cell physiology; Cells; Chemicals; Clinical; Cobalamin; Coumarins; Data; Effectiveness; Engineering; Enzymes; Exhibits; Fluorine; In Vitro; Methylation; Methyltransferase; Modification; Natural Products; Nature; Niacinamide; Nicotinamide N-Methyltransferase; Norepinephrine; Novobiocin; Organic Chemistry; Pathway interactions; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Process; Property; Protein Engineering; Publishing; Reaction; S-Adenosylmethionine; Source; Suggestion; Sulfur; Tellurium; Time; Work; alkyl group; analog; antitumor agent; carbanion; cyclopropane synthetase; design; human disease; improved; interest; methyl group; novel; novel strategies; scaffold; thioether

Project Summary Methyl groups are an important structural modification in natural products and are often essential for the effectiveness of natural products as antibacterial and/or antitumor agents. In nature, these methyl groups are most often appended by S-adenosylmethionine (SAM)-dependent methyltransferases (MTs) in a regioselective and stereoselective manner. This proposal focuses on transferring fluoromethyl and other fluorine-containing alkyl groups to natural products, because fluorine atoms have been shown to enhance the pharmacological effects of many drugs. In fact, about 20-30% of all drugs contain at least one fluorine atom. Strategies for introducing fluorine into biomolecules are therefore at the forefront of organic and medicinal chemistry. In this proposal, the the synthesis of novel fluoromethyl and difluoromethyl donors that have biological relevance is described. Indeed, we show that these fluorine-containing analogs of SAM, Te-adenosyl-(fluoromethyl)- telluromethionine (FMeTeSAM) and Te-adenosyl-(difluoromethyl)-telluromethionine (F2MeTeSAM) are acted upon by SAM-dependent MTs to transfer fluoroalkyl groups to target substrates, including catechol-O- methyltransferase-catalyzed O-fluoromethylation on dihydroxybenzoic acid and O-difluoromethylation on norepinephrine; nicotinamide N-methyltransferase-catalyzed N-fluoromethylation on nicotinamide; NovO- catalyzed C-fluoromethylation on coumarin; and 6-mercaptopurine methyltransferase-catalyzed S- difluoromethylation on 6-mercaptopurine. Ideally, this ability will be leveraged to modify methyl-containing natural products of clinical value (e.g. novobiocin and oxaline) with fluoromethyl groups in a facile manner at a late stage in their biosynthetic pathways, and to assess whether their pharmacological effects are improved. Other aims will focus on the enzymatic synthesis of β-fluoromethyl amino acids, which are found in a number of important antibiotics, as well as the addition of fluoromethyl groups to completely unactivated carbon centers via radical mechanisms.

项目摘要 甲基是天然产物中重要的结构修饰，通常对于 天然产物作为抗菌和/或抗肿瘤剂的有效性。在本质上，这些甲基是 最常见于调节性的S-腺苷硫氨酸（SAM）依赖性甲基转移酶（MTS） 和立体选择性。该提案着重于转移氟甲基和其他含氟 烷基的天然产物基团，因为氟原子已被证明可以增强药物 许多药物的影响。实际上，所有药物中约有20％至少含有一个氟原子。策略 因此，将氟引入生物分子是有机和医学化学的最前沿。在这个 提案，具有生物学相关性的新型荧光甲基和二氟甲基供体的合成是 描述。确实，我们表明这些含氟的Sam，Te-腺苷（荧光甲基） - 发作作用 通过SAM依赖性MT，将氟烷基基团转移到靶标底物，包括Catechol-O- 甲基转移酶催化的O-氟甲基化在二羟基苯甲酸上，O-二氟甲基化在 去甲肾上腺素；烟酰胺N-甲基转移酶催化的N-氟甲基化烟酰胺；诺 香豆素上催化的C-氟甲基化；和6-丙氨酸甲基转移酶催化的S- 6-丙氨酸的差甲基化。理想情况下，将利用这种能力来修饰含甲基的能力 临床价值的天然产物（例如，与荧光甲基的Novobiocin和草酸）在A 在生物合成途径的后期阶段，并评估其药理作用是否得到改善。 其他目的将集中于β-氟甲基氨基酸的酶促合成，这在数量中发现 重要的抗生素，以及在完全未活化的碳中添加荧光甲基 通过激进机制中心。