Laboratorio de Síntesis Orgánica, Departamento de Química Orgánica, Facultad de Química, Universidad de la República, General Flores 2124, Montevideo 11800, Uruguay.
Group Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, Mataojo 2020, Montevideo 11400, Uruguay.
Molecules. 2022 Jan 27;27(3):829. doi: 10.3390/molecules27030829.
The first stage of the drug discovery process involves the identification of small compounds with biological activity. Iboga alkaloids are monoterpene indole alkaloids (MIAs) containing a fused isoquinuclidine-tetrahydroazepine ring. Both the natural products and the iboga-inspired synthetic analogs have shown a wide variety of biological activities. Herein, we describe the chemoenzymatic preparation of a small library of novel -indolylethyl-substituted isoquinuclidines as iboga-inspired compounds, using toluene as a starting material and an imine Diels-Alder reaction as the key step in the synthesis. The new iboga series was investigated for its potential to promote the release of glial cell line-derived neurotrophic factor (GDNF) by C6 glioma cells, and to inhibit the growth of infective trypanosomes. GDNF is a neurotrophic factor widely recognized by its crucial role in development, survival, maintenance, and protection of dopaminergic neuronal circuitries affected in several neurological and psychiatric pathologies. Four compounds of the series showed promising activity as GDNF releasers, and a leading structure (compound ) was identified for further studies. The same four compounds impaired the growth of bloodstream (EC 1-8 μM) and two of them (compounds and ) showed a good selectivity index.
药物发现过程的第一阶段涉及具有生物活性的小分子化合物的鉴定。伊博格碱生物碱是含有稠合异喹啉-四氢吖啶环的单萜吲哚生物碱（MIAs）。天然产物和伊博格启发的合成类似物都显示出广泛的生物活性。在此，我们描述了使用甲苯作为起始原料和亚胺 Diels-Alder 反应作为合成关键步骤，通过酶促方法制备新型 -吲哚基乙基取代异喹啉的小文库，作为伊博格启发的化合物。该新伊博格系列被研究是否能够促进 C6 神经胶质瘤细胞释放胶质细胞系源性神经营养因子（GDNF），并抑制感染性锥虫的生长。GDNF 是一种神经营养因子，因其在几种神经和精神病理学中受影响的多巴胺能神经元回路的发育、存活、维持和保护中的关键作用而被广泛认可。该系列中的四种化合物作为 GDNF 释放剂表现出有希望的活性，并且确定了一种领先结构（化合物 ）用于进一步研究。这四种化合物都能抑制血液（EC 1-8 μM）的生长，其中两种（化合物 和 ）显示出良好的选择性指数。
