HALOGENATED BIOGENIC AMINES IN BIOCHEMISTRY AND PHARMACOLOGY

生物化学和药理学中的卤化生物胺

• 批准号: 6105218
• 负责人: KENNETH L KIRK
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6105218
• 关键词: alpha adrenergic agent; beta adrenergic agent; chemical structure function; chemical substitution; chemical synthesis; conformation; dopamine; epinephrine; fluorine; halogenation; neuropharmacology; neurotransmitter agonist; neurotransmitter antagonist; neurotransmitter metabolism; neurotransmitters; norepinephrine; prodrugs

Biogenic amines play key roles in neurotransmission, metabolism, and in control of various physiological processes. Using a variety of synthetic methodologies, including novel procedures developed by us, we have prepared a series of biogenic amines with fluorine substituted at various ring-positions. These ring-fluorinated biogenic amines continue to find applications in a multitude of studies, including research on the mechanisms of transport, storage, release, metabolism, and modes of action of these amines. Of particular significance was the discovery that 6-fluoronorepinephrine is a selective a-adrenergic agonist and 2-fluoronorepinephrine is a selective b-adrenergic agonist. Because our previous syntheses of FNEs produced racemic material, we have investigated routes to the pure R-enantiomers. Asymmetric aminohydroxylation of fluorostyrene precursors produced enantio-enriched fluorinated phenethanolamines, albeit with modest enantioselectivities. Highly enantioselective carbonyl reductions of fuorinated chloroketone intermediates with chiral boron catalysts (chemzymes), followed by side-chain elaboration, have provided a route to R-FNEs in good yield. Enantioselective cyanohydrin formation catalyzed by chiral salen catalysts, followed by reduction, is a second procedure we have developed. After final isolation and purification, receptor binding of the pure R- and S-isomers will be carried out to assess the effects of stereoisomerism on receptor selectivities. In order to have available alternate biological precursors for 2-FNE and 6-FNE, we previously synthesized threo-2- and 6-fluorodihydroxyphenylserine (fluoro-DOPS) in the racemic form, but found these analogues to be poor substrates for aromatic amino acid decarboxylase. We have prepared key precursors to the 2S,3R-isomers of fluorinated DOPS using Evans enantioselective aldol strategy. Fluorinated analogs of purine and pyrimidine bases are being prepared as potential P-site phosphodiesterase inhibitors, and as potential NMR probes for DNA structure and function.

生物胺在神经传递中发挥关键作用， 新陈代谢，并控制各种生理过程。 使用各种合成方法，包括新颖的 我们开发的程序，我们准备了一系列生物源 在不同环位上被氟取代的胺。这些 环氟化生物胺继续在以下领域找到应用： 大量研究，包括机制研究 运输、储存、释放、代谢和作用方式 这些胺。特别重要的是发现 6-氟去甲肾上腺素是一种选择性α-肾上腺素能激动剂 2-氟去甲肾上腺素是一种选择性β-肾上腺素能激动剂。因为 我们之前合成的 FNE 产生了外消旋材料，我们 研究了纯 R-对映异构体的路线。不对称 产生的氟苯乙烯前体的氨基羟基化 对映体富集的氟化苯乙醇胺，尽管含量适中 对映选择性。高度对映选择性羰基还原 手性硼催化剂的氟化氯酮中间体 （chemzymes），随后进行侧链阐述，提供了 通往 R-FNE 的路线，产率良好。对映选择性氰醇 由手性萨伦催化剂催化形成，然后还原， 是我们开发的第二个程序。最终隔离后 纯化后，纯R-和S-异构体的受体结合将被 进行评估立体异构现象对受体的影响 选择性。为了有可用的替代生物 2-FNE 和 6-FNE 的前体，我们之前合成 苏-2-和6-氟二羟基苯基丝氨酸（氟-DOPS） 外消旋形式，但发现这些类似物是不良底物 芳香族氨基酸脱羧酶。我们已经准备好了钥匙 使用 Evans 制备氟化 DOPS 2S,3R-异构体的前体 对映选择性羟醛策略。嘌呤的氟化类似物和 正在制备嘧啶碱基作为潜在的 P 位点 磷酸二酯酶抑制剂，并作为潜在的 NMR 探针 DNA 结构和功能。