基于知母皂苷元的神经甾体衍生物合成研究

更新时间:2023-06-01 21:13:00 阅读: 评论:0

摘 要
神经甾体是一类重要的中枢神经系统调节因子,能够对中枢神经系统产生重要的生理作用,神经甾体类药物具有治疗多种中枢神经系统疾病的潜力,如抗抑郁、抗癫痫等。
知母皂苷具有抗抑郁等神经药理活性。本课题组前期以知母皂苷元为先导化合物设计合成了系列衍生物并进行抗抑郁药理等研究,获得了YY-23等具有显著抗抑郁作用的化合物。知母皂苷元具有六环甾体骨架的结构特征,由知母皂苷元改造得到的四环甾体,分子量降低,分子的柔性增加,且与内源性神经甾体结构更加相近。同时,由知母皂苷元改造得到的四环甾体含有α,β-不饱和羰基,可以通过对不饱和羰基进行Michael加成,在C-16位进行结构改造,而目前文献报道的神经甾体结构改造工作少有涉及到C-16位。因此,本文基于知母皂苷元简化得到的四环甾体,对其C-3位和C-16位进行结构改造,设计合成结构新颖的神经甾体衍生物,并进行抗抑郁活性初步筛选,以期获得抗抑郁活性好、药代动力学特性改善的化合物。主要研究结果如下:
1. 四环甾体C-3位取代衍生物的设计合成
基于知母皂苷元的六环甾体骨架,将结构改造成四环甾体,并对C-3位采取了不同的结构修饰策略,包括:①在C-3位引入3α-乙酰氨基;②在C-3位引入3α-羟基-3β-甲基;③在C-3位引入3α-环己基脲基;④在A/B环反式基础上,C-3位引入3α-羟基-3β-甲基。这四种结构改造策略得到的4个四环甾体1/2/3/4,作
为下一步衍生物设计合成的中间体。
2. 四环甾体C-16位取代衍生物的设计合成
对于神经甾体衍生物的设计合成与结构改造,文献报道多集中在C-2、C-3、C-11、C-21位等。由于甾体骨架具有较强的疏水性,为了提高神经甾体的水溶性,通常会在甾体骨架上引入极性基团。上述4个四环甾体1/2/3/4均含有α, β-不饱和羰基,因此,可以通过氮杂Michael加成在C-16位引入含氮杂环,在C-16位进行结构改造。在目标产物的合成中,氮杂Michael加成是关键的反应步骤。文献报道以Cs2CO3为催化剂,在Dioxane中回流反应,可使吡唑与α,β-不饱和
羰基发生氮杂Michael加成。但为了避免高温回流生成目标产物的非对映异构体,我们用极性溶剂DMF替代Dioxane,反应可以在室温下顺利进行,且生成单一的目标产物。该反应条件不仅适用于吡唑,还适用于咪唑、1, 2, 4-三氮唑、1, 2, 3-三氮唑以及不同取代的吡唑,对芳香氮杂环适用范围广。
基于上述4个四环甾体1/2/3/4,通过对其α, β-不饱和羰基进行氮杂Michael 加成,在C-16位引入吡唑、咪唑、三氮唑、四氮唑、取代吡唑等含氮杂环,共合成了44个结构新颖的神经甾体衍生物。
3. 部分衍生物抗抑郁药理活性筛选
采用小鼠悬尾和强迫游泳两种经典的抗抑郁动物模型,对其中部分神经甾体衍生物进行抗抑郁活性初
步筛选。其中,化合物19在小鼠悬尾试验中能显著降低小鼠悬尾不动时间(p<0.05),在小鼠强迫游泳试验中能显著降低小鼠强迫游泳不动时间(p<0.05)。表明化合物19具有潜在的抗抑郁活性。
关键词:知母皂苷元,结构改造,神经甾体,抗抑郁
棕色系图片
Abstract
Neurosteroids are effective modulaters of the central nervous system (CNS) and can exert important physiological effects. Therefore, neurosteroids have the potential to treat CNS dias, such as anti-depression, anti-epilepsy and so on.
Sarsasapogenin has anti-depressant and other neuropharmacological activities. Our rearch group has been engaged in the design and synthesis of Sarsasapogenin derivatives and their antidepressant activities. We have abtained compound YY-23 with anti-depressant activities. Sarsasapogenin has the structural characteristic of the hexocyclic steroid skeleton. And the tetracyclic steroid modified from Sarsasapogenin has lower molecular weight, incread molecular flexibility, and is more similar to the structure of endogenous neurosteroids. At the same time, the tetracyclic steroid modified from Sarsasapogenin contains α,β-unsaturated carbonyl groups, which can be modified at the C-16 position through Michael addition. However, few studies on the structura
l modification of the neurosteroid involving the C-16 position have been reported so far. Therefore, in this thesis, bad on the tetracyclic steroids modified from Sarsasapogenin, the structure of the C-3 and C-16 positions was modified to design and synthesize the neurosteroid derivatives with novel structure. Then the antidepressant activity of some neurosteroid derivatives was preliminarily screened in order to obtain compounds with good antidepressant activity and improved pharmacokinetic properties. The main rearch results of this thesis are as follows:
1. Design and synthesis of C-3 substituent derivatives bad on tetracyclic steroids
Sarsasapogenin was simplified to tetracyclic steroid and modified at the C-3 position. The structural modification strategies of C-3 position include: (1) the introduction of 3α-acetylamino (2) the introduction of 3α-hydroxyl-3β-methyl (3) the introduction of 3-cyclohexyl urea group (4) on the basis of A/B ring trans, introducing 3α-hydroxyl-3β-methyl. Four tetracyclic steroids 1/2/3/4were obtained by the strategies, which were mainly ud as intermediates in the synthesis of other derivatives.
2. Design and synthesis of C-16 substituent derivatives bad on tetracyclic
steroids
高盐稀态发酵酱油In previous literatures, the structural modification sites are mainly C-2, C-3, C-11 and C-21. Due to the strong hydrophobicity of the steroid skeleton, polar groups are usually introduced into the steroid skeleton to improve the water solubility of the neurosteroids. Becau tetracyclic steroids 1/2/3/4 mentioned above contain α, β-unsaturated carbonyl, we can carry out structural modification at the C-16 position by aza-Michael addition. In the synthesis of the target products, the aza-Michael is the key step. In the literature, it has been reported that pyrazole can produce aza-Michael addition successfully using Cs2CO3 as the catalyst and dioxane as the solvent in the reflux condition. However, in order to avoid the formation of diastereoisomer of the target product in the reflux condition, dioxane was replaced with DMF, a polar solvent. The reaction could be conducted smoothly at room temperature and a single target product was generated. The reaction condition is applicable not only to pyrazole, but also to imidazole, 1, 2, 4-triazole, 1, 2, 3-triazole and substituted pyrazole, which has a wide range of application to aromatic heterocyclic compounds.
Bad on tetracyclic steroids mentioned 1/2/3/4, 44 novel neurosteroid derivatives were synthesized by the aza-Michael addition of the α, β-unsaturated carbonyl to introduce nitrogen-containing heterocycles, such as pyrazole, imidazole, triazoles, tetrazoles, and substituted pyrazoles, at the C-16 site.
那颗流星3. Screening of antidepressant pharmacological activities of some derivatives
Some derivatives were preliminarily screened for their antidepressant activity in two classic antidepressant animal models, tail suspension and forced swimming in mice. Oral administration of compound 19 significantly reduced the immobility time of tail suspension in mice (p<0.05). At the same time, oral administration of compound 19 significantly reduced the immobility time of forced swimming in mice (p<0.05). Therefore, compound 19 was shown to have potential antidepressant activity.
Key Words: Sarsasapogenin, Structural modification, Neurosteroids, Antidepressant
缩略词表
缩写英文全称中文全称
ALS Amyotrophic Lateral Sclerosis 肌萎缩性脊髓侧索硬化症
AMPA α-amino-3-hydroxy-5-methyl-4-isoxazole-
propionic acid
α-氨基-3-羟基-5-甲基-4-异恶
唑丙酸
CMC-Na sodium carboxyl methyl cellulo 羧甲基纤维素钠
DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene 1,8-二氮杂二环十一碳-7-烯DCE dichloroethane 二氯乙烷
DCM dichloromethane 二氯甲烷
DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone 2,3-二氯-5,6-二氰基-1,4-苯醌DIBAL-H diisobutylaluminum hydride 二异丁基氢化铝播放器
DIPEA N, N-diisopropylethylamine N,N-二异丙基乙胺
DMAP 4-dimethylaminopyridine 4-二甲氨基吡啶
彭读音DMF N, N-dimethylformamide N, N-二甲基甲酰胺
DMP Dess-Martin periodinane 戴斯马丁氧化剂
很火的短句
DMPK Drug Metabolism and Pharmacokinetics 药物代谢及药代动力学DMSO dimethyl sulfoxide 二甲基亚砜
EC50concentration for 50% of maximal effect 半最大效应浓度
ED5050% effective do 半数有效量
Fmoc fluorene methoxy carbonyl 芴甲氧羰基港珠澳大桥全长多少米
GABA γ-aminobutyric acid γ-氨基丁酸
HPβCD hydroxypropyl-β-cyclodextrin 羟丙基β环糊精
5-HT 5-hydroxytryptamine 5-羟色胺
IC50half maximal inhibitory concentration 半抑制浓度
IBX 2-Iodoxybenzoic acid 2-碘酰基苯甲酸
第一旅游MAD methyl aluminum bis-(2,6-di-tertbutyl-4-
methylphenoxide)
二(2,6-二叔丁基-4-甲基苯氧
基)甲基铝

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标签:甾体   结构   神经   抗抑郁   改造   衍生物   皂苷元   知母
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