Carson Matthew C, de Lima Neto Jorge, Duggal Kalyana B, Menezes Paulo H, Kozlowski Marisa C
Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323, United States.
Departamento de Química Fundamental, Universidade Federal de Pernambuco, Cidade Universitária, Recife, Pernambuco 50670-90, Brazil.
J Med Chem. 2025 Jul 24;68(14):14628-14644. doi: 10.1021/acs.jmedchem.5c00771. Epub 2025 Jul 7.
Aporphine alkaloids are important natural products with uses ranging from traditional Chinese herbal medicine to modern clinical applications. These compounds are isolated from a variety of plants and possess many powerful biological properties. Inspired by the biomimetic coupling of reticuline, we designed a novel synthetic approach to construct the corytuberine (8-2' coupling) and isoboldine (8-6' coupling) aporphine cores using a key photochemical intermolecular oxidative phenol coupling. With a short and efficient synthetic sequence telescoping of several intermediates (no chromatography) and minimal use of transition metals, we were able to functionalize these natural products into a variety of synthetic analogues. This fueled biological evaluation of the natural products and their derivatives for binding affinity at the serotonin 5-HT and adrenergic α receptors.
阿朴啡生物碱是重要的天然产物,其应用范围从传统中药到现代临床应用。这些化合物从多种植物中分离得到,并具有许多强大的生物学特性。受网叶番荔枝碱仿生偶联的启发,我们设计了一种新颖的合成方法,通过关键的光化学分子间氧化酚偶联来构建紫堇块茎碱(8-2' 偶联)和异波尔定碱(8-6' 偶联)阿朴啡核心结构。通过一个简短而高效的合成序列,将多个中间体进行缩合(无需柱色谱),并尽量少用过渡金属,我们能够将这些天然产物官能团化为多种合成类似物。这推动了对天然产物及其衍生物在血清素 5-HT 和肾上腺素能 α 受体上结合亲和力的生物学评价。