Structure-Activity Relationships of Neuritogenic Gentiside Derivatives
Structure-Activity Relationships of Neuritogenic Gentiside Derivatives
复制标题
致神经炎龙胆苷衍生物的构效关系
DOI：
10.1002/cmdc.201100348
复制
发表时间：
2011-11-04
期刊：
影响因子：
3.4
通讯作者：
Qi, Jianhua
中科院分区：
文献类型：
--
作者：
Luo, Yan;Sun, Kaiyue;Qi, Jianhua
Neurotrophic factors are target-derived peptides that play an important role in the development and survival of responsive neuronal populations. Nerve growth factor (NGF), one of the most important neurotrophic factors, is essential for neuronal differentiation, growth, survival, function maintenance, and prevention of aging in the central and peripheral systems.[1, 2] However, because of its large molecular size and hydrophilic properties, NGF cannot pass through the blood–brain barrier, limiting its use as a therapeutic agent. Therefore, synthetic low-molecular weight compounds that possess equivalent or better neuritogenic activity compared with NGF are promising agents for the treatment of neurodegenerative diseases, such as Alzheimer’s disease.[3] The PC12 cell line, cloned from rat pheochromocytoma, is widely used as a model system to evaluate the biological activity of neuritogenic substances.[4–7] Recently, screening for neuritogenic substances from traditional Chinese medicine resulted in the isolation of 11 novel alkyl benzoates (gentisides A–K) from Gentiana rigescens (Franch.).[8, 9] These compounds are structurally different from one another through varying alkyl chain lengths and the presence or absence of an isobutyl or isopropyl group at the end of the alkyl chain. The structure–activity relationships within gentisides reveal that the alkyl chain length is important for activity, but structural diversity at the end of the alkyl chain is not. Gentisides D, E, and F have similar alkyl chain lengths. In spite of the different structures at the end of the alkyl chain, these compounds exhibit similar neuritogenic activities at the optimum concentration of 3 μM. GentisideE, which has a straight alkyl chain of 18 carbon atoms, exhibits higher activity (74% at 3 μM) than gentiside K, which has 24 carbon atoms in the alkyl chain (48% at 30 μM).[9] To study the structure–activity relationships and discover lead compounds for drug development, a series of gentiside derivatives were designed and synthesized. First, 2, 3-dihydroxybenzoates 1a–j (Table1) with different alkyl chain lengths were synthesized to find the optimum length of the alkyl chain. Second, tetradecylbenzoates 1k–u (Table 1) were prepared to study the importance of the number and position of the hydroxy groups on the benzene ring. Third, to find the best linkage group between the benzene ring and alkyl chain, tetradecyl-benzamides 1v–y, phenylketones 2a–d, 2, 3-dihydroxyphenyl tetradecanoate (3 a) and 3-(tetradecyloxy) benzene-1, 2-diol (3 b) were synthesized. Full experimental details can be found in the Supporting Information. Ethyl-2, 3-dihydroxybenzoate 1a and pentyl-2, 3-dihydroxybenzoate 1b were prepared by reacting 2, 3-dihydroxybenzoic
