脉叶虎皮楠中新型生物碱的高效发现和抗疟疾活性研究★

doi:10.6023/A26070235

摘要/Abstract

将特征分子网络(FBMN)、SIRIUS机器学习辅助结构注释与高速逆流色谱相结合, 探索了FBMN与SIRIUS联合分析在虎皮楠生物碱(DAs)发现中的应用. 利用FBMN技术对三种虎皮楠属植物进行化学分析, 并结合SIRIUS平台对MS/MS特征进行系统注释, 筛选出脉叶虎皮楠(Daphniphyllum paxianum)作为研究对象, 其蕴含新颖且丰富DAs的潜力最大. 进一步采用低损耗分离策略(高速逆流色谱、凝胶色谱和高效液相色谱), 结合多种波谱解析方法以及基于量子力学的计算方法, 从中分离并鉴定了13个DAs, 包括3个新化合物(1~3)和10个已知化合物(4~13). 其中, 化合物1和2分别属于calyciphylline A型和daphnilactone B型DAs, 均含有氮杂双环[3.3.1]壬烷结构单元, 并且化合物2在C-2位发生了罕见的氧化修饰. 化合物3则属于罕见的daphnezomine F型DA, 其核心为氮杂双环[5.2.2]十一烷环系, 丰富了该类骨架的结构多样性. 抗疟疾活性结果显示化合物4可抑制氯喹耐药株Dd2 (Plasmodium falciparum Dd2)生长, IC₅₀为(27.7±3.7) μmol/L. 该研究表明, 以FBMN与SIRIUS联合导向为基础, 辅以低损耗分离手段, 为从复杂天然产物中高效、精准发现结构新颖且具有生物活性的DAs提供了有效途径.

关键词: 脉叶虎皮楠, 虎皮楠生物碱, 特征分子网络(FBMN), 高速逆流色谱(HSCCC), 结构解析, 抗疟疾活性

To accelerate the discovery of novel daphniphyllum alkaloids (DAs), an integrated workflow was developed that synergistically integrates feature-based molecular networking (FBMN), machine learning annotation powered by SIRIUS, and high-speed countercurrent chromatography (HSCCC) directed low-sample-loss separation. FBMN analysis was first performed on three Daphniphyllum species to profile their chemical space, leading to the selection of D. paxianum as the most promising source. Subsequent systematic annotation of MS/MS features using the SIRIUS platform predicted multiple known and potentially novel DAs, providing valuable guidance for targeted isolation. Guided by the FBMN and SIRIUS annotation results, a low-sample-loss separation protocol was subsequently implemented, which combined HSCCC, Sephadex LH-20 gel chromatography, and preparative HPLC. The targeted separation approach, in conjunction with comprehensive spectroscopic analysis (IR, HRESIMS, 1D and 2D NMR) and quantum-mechanical computational methods, enabled the efficient isolation and structural elucidation of 13 DAs from D. paxianum, of which three were identified as new compounds (1~3) with various skeletons, along with ten known analogues (4~13). Compounds 1 and 2 belong to the calyciphylline A-type and daphnilactone B-type DAs, respectively, both featuring a 2-azabicyclo[3.3.1]nonane core, with compound 2 characterized by rare C-2 oxidation. Compound 3 is a rare daphnezomine F-type DA with a 2-azabicyclo[5.2.2]undecane core, enriching the structural diversity of DAs. Evaluation of the antiplasmodial activity using SYBR Green Ⅰ method revealed that compound 4 inhibited the growth of the chloroquine-resistant P. falciparum Dd2 strain with a moderate IC₅₀ of (27.7±3.7) μmol/L. Concurrent biocompatibility assessment demonstrated that compound 4 was devoid of detectable cytotoxicity against A549 and HeLa cell lines (cell viability consistently exceeding 75% at 10 μmol/L) and exhibited negligible hemolytic activity (hemolysis rate <5% at 25 μmol/L). The unity of moderate antiplasmodial efficacy and excellent safety profile highlights compound 4 as a promising candidate for further structural optimization and mechanistic investigation as an antiplasmodial candidate compound. The research demonstrated that the FBMN and SIRIUS dual-guidance strategy, in combination with low-sample-loss separation, constitutes a powerful and efficient approach for the precise discovery of novel and bioactive DAs from complex natural materials.

Key words: Daphniphyllum paxianum, Daphniphyllum alkaloids, feature-based molecular networking (FBMN), high-speed countercurrent chromatography (HSCCC), structural elucidation, antiplasmodial activity

引用此文

吴佩茜, 左雨蝶, 许靖宜, 刘群芳, 周彬, 岳建民. 脉叶虎皮楠中新型生物碱的高效发现和抗疟疾活性研究^★[J]. 化学学报, 2026, 84(8): 1272-1282.

Peiqian Wu, Yudie Zuo, Jingyi Xu, Qunfang Liu, Bin Zhou, Jianmin Yue. Efficient Discovery of Novel Alkaloids from Daphniphyllum paxianum and Antiplasmodial Activity^★[J]. Acta Chimica Sinica, 2026, 84(8): 1272-1282.

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图/表 8

图1. 化合物1~3的结构

Figure 1. Structures of compounds 1~3

图2. (A)采用FBMN分析和SIRIUS注释对三种虎皮楠属植物生物碱部分进行化学成分系统性表征的技术流程、(B)利用Cytoscape构建的可视化分子网络、(C)目标DAs分子簇(簇一)[节点内字母(I~VIII)表示经SIRIUS预测注释的DAs, 节点旁数字表示前体离子质荷比(m/z)]及(D)经SIRIUS平台预测注释的已知DAs的分子结构以及其色谱保留时间和质谱峰

Figure 2. (A) Technical workflow for systematic characterization of the chemical components in the alkaloid fractions of three Daphniphyllum species using FBMN analysis and SIRIUS annotation, (B) visualization of the molecular network constructed using Cytoscape, (C) selected molecular network clusters of DAs (Cluster 1) [The numbers (I~VIII) within the nodes indicate the DAs annotated by SIRIUS prediction, and the numbers adjacent to the nodes represent the precursor ion masses (m/z)], and (D) structures of known DAs predicted and annotated by the SIRIUS platform, along with their chromatographic retention times and mass peaks

No.	1		2		3
	δ_H (J in Hz)	δ_C^a	δ_H (J in Hz)	δ_C^b	δ_H (J in Hz)	δ_C^a
1		216.5	3.84, s	71.5		176.6
2	2.45, m	43.0		77.0	3.53, dt (10.3, 3.4)	73.3
3	a 2.64, br dd (16.1, 4.8)	19.3	α 1.94, m	27.9	α 1.94, ddt (16.6, 13.2, 3.6)	39.6
	b 2.56, ddd (16.1, 4.7, 1.6)		β 1.71, m		β 1.60, ddt (16.6, 5.9, 3.2)
4	4.01, dt (4.7, 2.0)	88.2	2.10~2.16, m	31.0	1.68~1.70, m	44.7
5		53.4		42.4		43.2
6	2.94, m	48.0	2.49, overlapped	38.7	2.40, overlapped	41.9
7	α 3.49, t (13.1)	70.0	a 3.40, dd (14.7, 1.8)	57.9	α 3.71, dd (13.8, 7.9)	52.3
	β 3.26, dd (12.6, 6.0)		b 3.57, dd (14.7, 10.7)		β 3.49, dd (13.8, 10.7)
8		67.4		42.4		58.4
9		185.1		151.6		139.8
10	3.62, br s	38.1	2.99, m	48.4		135.7
11	α1.68, m	24.7	α 1.54, dd (13.4, 4.2)	33.2	2.26-2.30, m	25.4
	β 1.57, m		β 1.73, m
12	α1.79, m	20.7	α 1.42, m	30.6	α 1.66, overlapped	26.4
	β 1.74, m		β 2.10, m		β 2.23, overlapped
13	α 2.32, dt (13.5, 8.9)	40.5	a 1.98, m	29.4	α 2.49, dd (13.0, 8.6)	35.8
	β 3.02, m		b 2.22, overlapped		β 2.33, dd (13.0, 7.6)
14	2.37~2.40, m	25.4	a 2.24, overlapped	30.7	3.20, ddd (11.4, 8.6, 7.6)	43.4
			b 2.44, m
15		153.3	5.84, t (2.5)	131.5	3.30, overlapped	54.2
16		205.7	α 2.54, m	30.2	α 1.89, dt (11.8, 6.9)	29.7
			β 2.23, overlapped		β 1.21, dtd (11.8, 10.5, 8.6)
17	α 2.99, dd (18.1, 6.1)	49.6	α 1.62, dd (12.5, 8.0)	33.5	α 2.49, overlapped	43.0
	β 2.48, dd (18.1, 3.6)		β 2.10, m		β 2.22, overlapped
18	2.59, m	32.7	2.40, m	44.2	2.13, dddq (10.3, 9.0, 8.1, 6.9)	39.2
19	α 3.16, dd (13.3, 10.8)	67.1	a 4.06, dd (12.8, 11.0)	63.5	α 4.32, dd (14.0, 8.1)	54.1
	β 3.73, dd (13.3, 7.0)		b 2.78, dd (12.8, 8.9)		β 2.39, dd (14.0, 9.0)
20	1.21, d (6.8)	19.5	1.09, d (6.9)	11.1	0.94, d (6.9)	18.1
21	1.44, s	22.8	a 4.29, d (10.7)	66.5	1.15, s	25.4
			b 3.61, d (10.7)
22				175.9		177.3
23			3.62, s	52.1	3.63, s	51.8

No.	1		2		3
	δ_H (J in Hz)	δ_C^a	δ_H (J in Hz)	δ_C^b	δ_H (J in Hz)	δ_C^a
1		216.5	3.84, s	71.5		176.6
2	2.45, m	43.0		77.0	3.53, dt (10.3, 3.4)	73.3
3	a 2.64, br dd (16.1, 4.8)	19.3	α 1.94, m	27.9	α 1.94, ddt (16.6, 13.2, 3.6)	39.6
	b 2.56, ddd (16.1, 4.7, 1.6)		β 1.71, m		β 1.60, ddt (16.6, 5.9, 3.2)
4	4.01, dt (4.7, 2.0)	88.2	2.10~2.16, m	31.0	1.68~1.70, m	44.7
5		53.4		42.4		43.2
6	2.94, m	48.0	2.49, overlapped	38.7	2.40, overlapped	41.9
7	α 3.49, t (13.1)	70.0	a 3.40, dd (14.7, 1.8)	57.9	α 3.71, dd (13.8, 7.9)	52.3
	β 3.26, dd (12.6, 6.0)		b 3.57, dd (14.7, 10.7)		β 3.49, dd (13.8, 10.7)
8		67.4		42.4		58.4
9		185.1		151.6		139.8
10	3.62, br s	38.1	2.99, m	48.4		135.7
11	α1.68, m	24.7	α 1.54, dd (13.4, 4.2)	33.2	2.26-2.30, m	25.4
	β 1.57, m		β 1.73, m
12	α1.79, m	20.7	α 1.42, m	30.6	α 1.66, overlapped	26.4
	β 1.74, m		β 2.10, m		β 2.23, overlapped
13	α 2.32, dt (13.5, 8.9)	40.5	a 1.98, m	29.4	α 2.49, dd (13.0, 8.6)	35.8
	β 3.02, m		b 2.22, overlapped		β 2.33, dd (13.0, 7.6)
14	2.37~2.40, m	25.4	a 2.24, overlapped	30.7	3.20, ddd (11.4, 8.6, 7.6)	43.4
			b 2.44, m
15		153.3	5.84, t (2.5)	131.5	3.30, overlapped	54.2
16		205.7	α 2.54, m	30.2	α 1.89, dt (11.8, 6.9)	29.7
			β 2.23, overlapped		β 1.21, dtd (11.8, 10.5, 8.6)
17	α 2.99, dd (18.1, 6.1)	49.6	α 1.62, dd (12.5, 8.0)	33.5	α 2.49, overlapped	43.0
	β 2.48, dd (18.1, 3.6)		β 2.10, m		β 2.22, overlapped
18	2.59, m	32.7	2.40, m	44.2	2.13, dddq (10.3, 9.0, 8.1, 6.9)	39.2
19	α 3.16, dd (13.3, 10.8)	67.1	a 4.06, dd (12.8, 11.0)	63.5	α 4.32, dd (14.0, 8.1)	54.1
	β 3.73, dd (13.3, 7.0)		b 2.78, dd (12.8, 8.9)		β 2.39, dd (14.0, 9.0)
20	1.21, d (6.8)	19.5	1.09, d (6.9)	11.1	0.94, d (6.9)	18.1
21	1.44, s	22.8	a 4.29, d (10.7)	66.5	1.15, s	25.4
			b 3.61, d (10.7)
22				175.9		177.3
23			3.62, s	52.1	3.63, s	51.8

表1. 化合物1~3在CD3OD中的1H NMR (600 MHz)和13C NMR数据

Table 1. 1H (600 MHz) and 13C NMR data of compounds 1~3 in CD3OD

表1. 化合物1~3在CD3OD中的1H NMR (600 MHz)和13C NMR数据

Table 1. 1H (600 MHz) and 13C NMR data of compounds 1~3 in CD3OD

图3. 化合物1~3关键的1H-1H COSY、HMBC和NOESY相关

Figure 3. Key 1H-1H COSY, HMBC, and NOESY correlations of compounds 1~3

图4. 化合物1~3的实验和计算ECD谱图

Figure 4. Experimental and ECD spectra of compounds 1~3

图5. 计算与实验13C NMR化学位移之间的线性相关图

Figure 5. Linear correlation plots between the calculated and experimental 13C NMR chemical shifts

Possible isomer	(2R*)-2	(2S*)-2
DP4＋ (H data)	9.65%	90.35%
DP4＋ (C data)	0.00%	100.00%
DP4＋ (all data)	0.00%	100.00%

表2. (2R*)-2和(2S*)-2的DP4＋概率结果

Table 2. DP4＋ probability for (2R*)-2 and (2S*)-2

图6. (A)化合物1~13对红细胞溶血作用的96孔板观察结果、(B)化合物1~13的血液相容性评价、(C)化合物1~13对两种肿瘤细胞株的增殖抑制作用以及对P. falciparum Dd2的生长抑制作用及(D)活性化合物4与阳性对照对P. falciparum Dd2无性血期的剂量效应曲线[结果以平均值±SD表示(n=3)]

Figure 6. (A) Visual inspection of RBC hemolysis induced by compounds 1~13 in 96‑well plates, (B) hemocompatibility evaluation of compounds 1~13, (C) cytotoxicity of compounds 1~13 against two tumor cell lines and their inhibitory activity against P. falciparum Dd2, and (D) dose‑response curve of compound 4 and positive controls against the asexual blood stages of P. falciparum Dd2 [The results were expressed as mean±SD (n=3)]

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