含苯并咪唑结构的薁类衍生物的设计合成及抗炎活性研究

doi:10.6023/cjoc202302007

摘要/Abstract

苯并咪唑(BI)结构广泛存在于多种生物活性化合物中, 在药物合成领域受到越来越多的关注. 薁类衍生物是一类可从药用植物中获得的天然产物, 具有抗炎、抗氧化及低毒等特点. 以薁类衍生物与BI为原料, 通过Buchwald- Hartwig偶联得到了14个含苯并咪唑结构的薁类衍生物, 并研究了其抗炎活性和构效关系. 结果表明, 这些化合物能有效抑制脂多糖(LPS)诱导的巨噬细胞中NO的产生, 具有比愈创木薁磺酸钠(GAS-Na)更好的抗炎活性. 其中有三个薁类衍生物具有低毒性和高抗炎效果, 酶联免疫吸附测定法(ELISA)表明其以浓度依赖性的方式抑制LPS诱导的肿瘤坏死因子α (TNF-α)和白细胞介素6 (IL-6)的释放. 研究表明1-愈创木薁-苯并咪唑(GABI-1)具有高抗炎活性(给药浓度为20 μmol/L时的NO抑制率为33.69%)和低细胞毒性, 有望成为新型抗炎药候选分子.

关键词: 薁, 愈创木薁, 苯并咪唑, 愈创木薁磺酸钠, 抗炎活性

Benzimidazole (BI) unit exists in many bioactive compounds and has attracted more and more attention in the field of drug synthesis. Azulene derivatives are natural products obtained from medicinal plants, which have the characteristics of anti-inflammatory, antioxidant, and low toxicity. Using azulene derivatives and BI as raw materials, fourteen azulene derivatives that contain benzimidazole unit were synthesized by using Buchwald-Hartwig coupling strategy. Then their anti-inflammatory activity and structure-activity relationship were studied. The results showed that these compounds can effectively inhibit the production of NO in lipopolysaccharide (LPS) induced macrophages and have higher anti-inflammatory activity than sodium guaiazulene sulfonate (GAS-Na). Among them, three derivatives were screened with low toxicity and high anti-inflammatory activity, and they can inhibit the release of LPS-induced interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in a dose-dependent manner by enzyme-linked immunosorbent assay (ELISA). The results show that 1-guaiaculene benzimidazole (GABI-1) has high anti-inflammatory activity (the inhibitory rate of NO was 33.69% at the doses of 20 μmol/L) and low cytotoxicity, which is expected to become a candidate molecule for new anti-inflammatory drugs.

Key words: azulene, guaiazulene, benzimidazole, sodium guaiazulene sulfonate, anti-inflammatory activity

引用此文

肖梦佳, 高希珂. 含苯并咪唑结构的薁类衍生物的设计合成及抗炎活性研究[J]. 有机化学, 2023, 43(9): 3246-3256.

Mengjia Xiao, Xike Gao. Design, Synthesis and Anti-inflammatory Activity of Azulene Derivatives Containing Benzimidazole Unit[J]. Chinese Journal of Organic Chemistry, 2023, 43(9): 3246-3256.

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图/表 7

图1. 苯并咪唑、薁和愈创木薁的结构式

Figure 1. Chemical structures of benzimidazole, azulene and guaiazulene

Entry	Solvent	Catalyst	Ligand	Base	Temp./℃	Yield^b/%
1	Toluene	Pd₂(dba)₃	Davephos	NaO^tBu	110	49
2	Toluene	Pd₂(dba)₃	Xphos	NaO^tBu	110	80
3	Toluene	Pd₂(dba)₃	Sphos	NaO^tBu	110	80
4	Toluene	Pd₂(dba)₃	Me^tBu-Xphos	NaO^tBu	110	5
5	Toluene	Pd₂(dba)₃	^tBu-Xphos	NaO^tBu	110	85
6	Toluene	Pd(OAc)₂	^tBu-Xphos	NaO^tBu	110	79
7	Toluene	Pd(dppf)Cl₂	^tBu-Xphos	NaO^tBu	110	74
8	Toluene	Pd₂(dba)₃	^tBu-Xphos	K₂CO₃	110	24
9	Toluene	Pd₂(dba)₃	^tBu-Xphos	Cs₂CO₃	110	67
10	Toluene	Pd₂(dba)₃	^tBu-Xphos	K₃PO₄	110	30
11	1,4-Dioxane	Pd₂(dba)₃	^tBu-Xphos	NaO^tBu	110	83
12	DMB	Pd₂(dba)₃	^tBu-Xphos	NaO^tBu	110	82

表1. Buchwald-Hartwig偶联反应条件优化a

Table 1. Optimization of Buchwald-Hartwig coupling reaction conditions

图式1. GABI-1 ~GABI-7和AzBI-1~AzBI-7的合成路线

Scheme 1. Synthesis routes of GABI-1~GABI-7 and AzBI-1~AzBI-7

图2. 化合物GABI-2和GABI-7的单晶结构

Figure 2. X-Ray single crystal structures of products GABI-2 and GABI-7

图3. 不同化合物对LPS诱导的RAW 264.7细胞NO的抑制活性

Figure 3. Inhibitory activities against NO of the different compounds in LPS-induced RAW 264.7 cells Data are given as mean±SEM. *p<0.05 compared to GAS-Na

图4. 化合物对巨噬细胞RAW 264.7细胞存活率的影响

Figure 4. Effects of compounds on the cell viability of macrophage RAW 264.7 cells

图5. 不同化合物对LPS诱导的RAW 264.7细胞TNF-α和IL-6的抑制活性

Figure 5. Inhibitory activities against TNF-α and IL-6 of the different compounds in LPS-induced RAW 264.7 cells Data are given as mean±SEM. (a, b) Inhibition of LPS-induced TNF-α and IL-6 of compounds GABI-1, GABI-2, GABI-3, GABI-5, and GABI-6 at 20 μmol/L; (c, d) inhibition of LPS-induced TNF-α and IL-6 of compounds GABI-1, GABI-2, GABI-6. Data are expressed as fold change relative to control values (samples treated with LPS alone). ****p<0.0001, ***p<0.001, **p<0.01, *p<0.05 compared to LPS.

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