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

项目摘要 甲基是天然产物中重要的结构修饰，并且通常对于天然产物的合成是必需的。 天然产物作为抗菌剂和/或抗肿瘤剂的有效性。在自然界中，这些甲基是 最常见的附加有S-腺苷甲硫氨酸（SAM）依赖性甲基转移酶（MT）， 和立体选择性的方式。该提案的重点是转移氟甲基和其他含氟化合物 烷基，因为氟原子已被证明可以增强药理学活性， 许多药物的作用。事实上，大约20-30%的药物含有至少一个氟原子。战略 因此，将氟引入生物分子是有机化学和药物化学的前沿。在这 本发明提出了一种具有生物相关性的新型氟甲基和二氟甲基供体的合成方法， 介绍了事实上，我们表明，这些含氟类似物的SAM，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（F2 MeTeSAM）起作用， 通过SAM依赖性MT将氟烷基转移到目标底物，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 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; NovO- 催化的香豆素上的C-氟甲基化;和6-巯基嘌呤甲基转移酶催化的S- 6-巯基嘌呤上的二氟甲基化。理想地，将利用这种能力来修饰含甲基的聚硅氧烷。 具有临床价值的天然产物（如新生霉素和恶嗪）， 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。 其他目标将集中于β-氟甲基氨基酸的酶促合成，其存在于许多文献中。 重要的抗生素，以及氟甲基基团添加到完全未活化的碳 通过激进的机制。

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.