Synthesis and Anti-neuroinflammatory Activities of 25-Hydroxycholesterol and Its Analogues

doi:10.6023/cjoc202312002

Abstract

25-Hydroxycholesterol (25HC) has many important biological activities and is also a key intermediate for the synthesis of calcifediol, calcitriol, etc. It is of great significance to develop a new synthetic route which is easy to available raw materials, simple process, and easy to scale up. In this report, three 25-hydroxycholesterol and its analogues were synthesized from hyodeoxycholic acid via esterification of hydroxyl groups, decarboxylation iodization of carboxyl groups, ketonic hydrolysis after nucleophilic substitution with α-ketoester, sulfonate esterification then elimination, and finally reaction with Grignard reagent. The total yield was 20.8%~23.0%. The new route is simple to operate and easy to scale up, and is expected to be further developed into an industrial synthetic route. Similar analogues of 25-hydroxycholesterol can be easily prepared by changing α-ketoesters and Grignard reagents. Among the 15 compounds synthesized, there are 9 new compounds. Their biological activities were evaluated. The results showed that 26,27-diethylcholest-5-ene-3β,25-diol (8c) has good anti-neuritis activity and can inhibit NO release from LPS (lipopolysaccharides)-induced BV-2 (mouse microglia) cells by inhibiting Nuclear Factor kappa-B (NF-κB) and Mitogen-activated protein kinase/c-Jun N-terminal Kinase (MAPK/JNK) signaling pathways, and down-regulating mRNA-levels of inflammatory cytokines such as Interleukin-6 (IL-6), Tumor Necrosis Factor-α (TNF-α) and Interleukin-1β (IL-1β), indicating that 8c is a potential anti-neuroinflammatory compound.

Key words: 25-hydroxycholesterol, 25-hydroxycholesterol analogues, synthesis, anti-neuritis activity

Cite this article

Liusong Lan, Qian Yang, Yongyi Li, Shujun Fang, Yuxuan Huang, Juncheng Su, Chengxue Pan, Guifa Su. Synthesis and Anti-neuroinflammatory Activities of 25-Hydroxycholesterol and Its Analogues[J]. Chinese Journal of Organic Chemistry, 2024, 44(7): 2305-2314.

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Compd.	Survival rate/%	Compd.	Survival rate/%
4a	102.64±5.45	6c	121.65±3.41***
4b	3.84±0.36****	7a	120.48±3.71***
4c	3.26±0.04****	7b	98.38±4.58
5a	54.69±17.96*	7c	118.12±3.15***
5b	4.06±0.57****	8a	27.52±0.69****
5c	4.12±0.51****	8b	23.97±3.76****
6a	104.09±4.36	8c	112.82±8.91
6b	120.31±4.51**	Control	100±2.56
HDCA	102.18±8.06	DEX	85.05±2.84***

Compd.	Survival rate/%	Compd.	Survival rate/%
4a	102.64±5.45	6c	121.65±3.41***
4b	3.84±0.36****	7a	120.48±3.71***
4c	3.26±0.04****	7b	98.38±4.58
5a	54.69±17.96*	7c	118.12±3.15***
5b	4.06±0.57****	8a	27.52±0.69****
5c	4.12±0.51****	8b	23.97±3.76****
6a	104.09±4.36	8c	112.82±8.91
6b	120.31±4.51**	Control	100±2.56
HDCA	102.18±8.06	DEX	85.05±2.84***

Compd.	Release of nitric oxide/%	Compd.	Release of nitric oxide/%
4a	76.18±13.74*	7a	59.70±8.25**
6a	61.16±11.65**	7b	61.16±5.53***
6b	45.78±23.93*	7c	71.78±8.25**
6c	39.55±16.41**	8c	12.98±6.31****
Control	12.82±8.25	DEX	30.03±8.32***
LPS	100±7.20^####	HDCA	56.62±6.42

Compd.	Release of nitric oxide/%	Compd.	Release of nitric oxide/%
4a	76.18±13.74*	7a	59.70±8.25**
6a	61.16±11.65**	7b	61.16±5.53***
6b	45.78±23.93*	7c	71.78±8.25**
6c	39.55±16.41**	8c	12.98±6.31****
Control	12.82±8.25	DEX	30.03±8.32***
LPS	100±7.20^####	HDCA	56.62±6.42

Compd.	Survival rate/%	Compd.	Survival rate/%
4a	43.54±2.98****	7a	1.90±0.12****
6a	25.64±2.75****	7b	1.33±0.41****
6b	26.14±5.74****	7c	1.60±0.21****
6c	6.47±1.30****	8c	56.22±1.30****
Control	100±1.19	DEX	14.37±2.93****
LPS	88.57±2.01

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