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: 10196336
• 负责人: SQUIRE J. BOOKER
• 金额: $ 18.9万
• 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 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10196336
• 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; Structure; 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.

项目概要 甲基是天然产物中重要的结构修饰，通常对于天然产物的合成至关重要。 天然产物作为抗菌剂和/或抗肿瘤剂的功效在自然界中，这些甲基是。 最常以区域选择性方式附加 S-腺苷甲硫氨酸 (SAM) 依赖性甲基转移酶 (MT) 该提案的重点是转移氟甲基和其他含氟物质。 烷基到天然产物中，因为氟原子已被证明可以增强药理作用 事实上，大约20-30%的药物至少含有一个氟原子。 因此，将氟引入生物分子处于有机化学和药物化学的前沿。 建议，具有生物相关性的新型氟甲基和二氟甲基供体的合成是 事实上，我们证明了 SAM 的这些含氟类似物，Te-腺苷-(氟甲基)-。 碲甲硫氨酸 (FMeTeSAM) 和 Te-腺苷-(二氟甲基)-碲甲硫氨酸 (F2MeTeSAM) 起作用 通过 SAM 依赖性 MT 将氟烷基转移至目标底物，包括儿茶酚-O- 甲基转移酶催化的二羟基苯甲酸的O-氟甲基化和O-二氟甲基化 去甲肾上腺素；烟酰胺 N-甲基转移酶催化的烟酰胺 N-氟甲基化； 香豆素催化的 C-氟甲基化；和 6-巯基嘌呤甲基转移酶催化的 S- 理想情况下，可以利用这种能力来修饰 6-巯基嘌呤上的甲基。 具有临床价值的天然产物（例如新生霉素和奥沙林）以简便的方式在 其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。 其他目标将集中在 β-氟甲基氨基酸的酶促合成上，这种氨基酸存在于许多化合物中。 重要的抗生素，以及在完全未活性炭中添加氟甲基 通过激进机制中心。