Chinese Chemical Letters  2024, Vol. 35 Issue (6): 108927   PDF    
Citation
Zhang Ji, Zhang Tong, An Qiao, Zhang Peng, Tian Cai-Yan, Yuan Chun-Mao, Yi Ping, Hu Zhan-Xing, Hao Xiao-Jiang. Five quinolizidine alkaloids with anti-tobacco mosaic virus activities from two species of Sophora[J]. Chin. Chem. Lett., 2024, 35(6): 108927  
Five quinolizidine alkaloids with anti-tobacco mosaic virus activities from two species of Sophora
Ji Zhanga,b,c,1, Tong Zhanga,b,c,1, Qiao Ana,b, Peng Zhanga,b, Cai-Yan Tiana,b,d, Chun-Mao Yuana,b, Ping Yia,b, Zhan-Xing Hua,b,*, Xiao-Jiang Haoa,b,e,f,*     
a State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China;
b Natural Products Research Center of Guizhou Province, Guiyang 550014, China;
c School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550025, China;
d School of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China;
e State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Science, Kunming 650201, China;
f Research Unit of Chemical Biology of Natural Anti-Virus Products, Chinese Academy of Medical Sciences, Kunming 650201, China
Received 24 June 2023, Received in revised form 8 August 2023, Accepted 10 August 2023, Available online 12 August 2023
* Corresponding authors.
E-mail addresses: huzhxi88@163.com (Z.-X. Hu), haoxj@mail.kib.ac.cn (X.-J. Hao).
1 These authors contributed equally to this work.
Abstract: Three novel matrine-type alkaloids (1–3) and two unprecedented aloperine-type alkaloids (4 and 5) were isolated from the root of Sophora tonkinensis and the seeds of Sophora alopecuroides respectively. Notably, compound 1 possessed an unprecedented 6/5/6 tricyclic skeleton, while compounds 2 and 3 characterized by rare 6/6/5/6 tetracyclic system and 6/6/6/6/6 pentacyclic system respectively. Moreover, compound 4 possessed an unprecedented 6/7/6/6 tetracyclic core, and compound 5 characterized by rare 6/6/6/6 tetracyclic skeleton. Their structures were elucidated by comprehensive spectroscopic data analysis and electronic circular dichroism (ECD) calculations. Biological tests indicated that compound 5 displayed significant anti-tobacco mosaic virus (TMV) activity compared with the positive control ningnanmycin.
Keywords: Matrine-type alkaloids    Aloperine-type alkaloids    Sophora tonkinensis    Sophora alopecuroides    Anti-tobacco mosaic virus    

Quinolizidine alkaloids (QAs) are characteristic natural products of many Fabaceae, especially abundant in the tribes Genisteae, Sophoreae, and Thermopsideae [1–5]. They are biosynthesized from L-lysine through the decarboxylated intermediate cadaverine, which undergoes a series of enzymatic reactions to form different types of QAs, such as matrine-type, aloperine-type, cytisine-type, anagyrine-type, thermopsine-type, and sparteine-type [6–8]. QAs have been reported to have various biological activities including antibacterial, anti-inflammatory, antiviral, anti-allergic, and antitumor activities [9–17]. Previously, we found several new QAs with anti-plant virus activities from the seeds of T. lanceolata [18,19]. In our continuing efforts to discover novel, highly effective antiviral agents from QAs, the chemical components of the root of S. tonkinensis and the seeds of S. alopecuroides were carried out, which led to the isolation of three novel matrine-type alkaloids (1–3) and two unprecedented aloperine-type alkaloids (4 and 5) respectively. Notably, compounds 1–3 possessed unprecedented 6/5/6 tricyclic system, 6/6/5/6 tetracyclic skeleton, and 6/6/6/6/6 pentacyclic frame respectively. In addition, compound 4 possessed an unprecedented 6/7/6/6 tetracyclic skeleton, while compound 5 characterized by rare 6/6/6/6 tetracyclic skeleton (Fig. 1). The anti-tobacco mosaic virus (TMV) activities of isolates were screened using the half-leaf method. Herein, the isolation, structural determinations, and bioactivity assays were described.

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Fig. 1. Structures of compounds 1–5.

Sophortonkine A (1) with the molecular formula of C11H12N2O on the basis of the high resolution electrospray ionization mass spectroscopy (HRESIMS) (m/z 211.0846 [M + Na]+, calcd. for 211.0842). The nuclear magnetic resonance (NMR) data of 1 displayed a pyridine ring [δC 157.9, 149.6 (δH 8.54, d, J = 4.9 Hz), 134.2, 129.7 (δH 7.54, d, J = 7.7 Hz), 122.4 (δH 7.24, dd, J = 7.7, 4.9 Hz)] (Tables S1 and S2 in Supporting information). Moreover, the 1H–1H correlation spectroscopy (COSY) correlations of H-6/H2-7/H2-8/H2-9, combined with the heteronuclear multiple bond correlation spectroscopy (HMBC) correlations from H2-12 to C-5 (δC 134.2)/C-6 (δC 61.9)/C-10 (δC 169.0)/C-13 (δC 157.9), from H-9 to C-10, and from H-6 to C-5 indicated the existence of hexahydro-5(1H)-indolizinone unit (rings B and C) (Figs. 1 and 2) [20]. Furthermore, the key HMBC correlations from H2-12 to C-5/C-13, and from H-4 to C-6/C-13 demonstrated that above two units were fused via the C5–C13 bond (Fig. 2). Therefore, compound 1 with a rare 6/5/6 tricyclic ring system.

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Fig. 2. The key HMBC, 1H–1H COSY, and NOESY of 1–5.

The absolute configuration of 1 was further verified through electronic circular dichroism (ECD) calculations [21]. As a result, the calculated ECD spectrum of (6R)−1 matched well with the experimental circular dichroism (CD) spectrum of 1 (Fig. 3). Therefore, the absolute configuration of the stereogenic center of 1 was assigned as 6R.

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Fig. 3. Experimental and calculated ECD spectra of 1–5.

Sophortonkine B (2) was obtained as colorless oil. Its molecular formula, C14H22N2O3, was determined by the HRESIMS (m/z : 289.1539 [M + Na]+, calcd. 289.1528). The 1H NMR spectrum of 2 showed the signals of two nitrogenated methines (δH 2.26, m, H-6; δH 4.20, d, J = 10.6 Hz, H-11) and two nitrogenated methenes (δH 2.72, m, H2-2a; δH 2.28, m, H2-2b; δH 2.74, m, H2-10a; δH 2.25, m, H2-10b). The 13C and heteronuclear single quantum correlation spectroscopy (HSQC) spectra revealed 14 carbon signals due to one sp2 quaternary carbon, two sp3 quaternary carbons, two sp3 methines, and nine sp3 methylenes (Tables S1 and S2). The 1H–1H COSY correlations of H2-2/H2-3/H2-4 and H2-8/H2-9/H2-10, together with the HMBC correlations of H-6 to C-2 (δC 52.4)/C-7 (δC 76.6)/C-10 (δC 53.8), of H2-4 to C-5 (δC 92.1)/C-6 (δC 72.7), and of H2-8 to C-7 displayed the presence of quinolizidine core (rings A and B) (Figs. 1 and 2) [22]. Meanwhile, the 1H–1H COSY correlations of H-11/H2-12/H2-13/H2-14, and the HMBC correlations of H-14 to C-15 (δC 173.7), of H-6 to C-7/C-11 (δC 64.6), and of H2-12 to C-7 indicated the existence of hexahydro-5(1H)-indolizinone moiety (rings C and D) (Figs. 1 and 2) [23]. Moreover, the HMBC correlations of H-6 to C-11/C-7, of H-8 and H2-12 to C-7, and of H2-4 to C-5/C-6 indicated the above two moieties were connected via the C5–C6–C7 bond. Thus, the unique 6/6/5/6 tetracyclic core have been formed on the basis of the fragments established above. Furthermore, the key HMBC correlations of 5-OH to C-5/C-6, and of 7-OH to C-7/C-8 demonstrated that two hydroxyl groups were connected to C-5 and C-7 respectively (Fig. 2).

The nuclear overhauser effect spectroscopy (NOESY) correlations of H-11/H2-13b, H-11/H2-8b, H2-8b/H2-9a, and H2-9b/H-6 indicated that H-11 and H-6 were β- and α-oriented respectively. Meanwhile, the correlations of H2-4b/H-11 and H2-8b/H-11 revealed that C-5 and C-7 were all S*. The absolute configuration of 2 was established as (5S, 6R, 7S, 11R) by the aforementioned evidence, the biosynthetic pathway, and X-ray diffraction analysis of biogenic homologue [20,23]. Moreover, the absolute configuration of 2 was further verified through ECD calculations (Fig. 3).

Sophtonkine C (3) was obtained as colorless oil. Its molecular formula was deduced to be C19H28N2O2, by HRESIMS (m/z 317.2220 [M + H]+, calcd. 317.2224). The 13C and HSQC spectroscopic data revealed the presence of total 19 carbon resonances, corresponding to two sp2 quaternary carbons, two sp3 quaternary carbons, two sp3 methines, and thirteen sp3 methylenes (Table S2). The aforementioned evidence suggested that compound 3 was an analogue of matrine [24]. The notable difference was that an additional butan-2-one group (δC 30.8, 34.7, 37.0, 211.9) was fused between C-5 (δC 36.1) and C-6 (δC 62.6), which was supported by the 1H–1H COSY correlation H2-18/H2-19, and the obvious HMBC correlations between H2-18/H2-19/H2-21 and C-20 (δC 211.9), between H2-18 and C-4 (δC 28.7)/C-5/C-17 (δC 45.2), and between H2-21 and C-6/C-7 (Fig. 2). Thereby, compound 3 possessed an undescribed 6/6/6/6/6 pentacyclic skeleton.

The NOESY correlations of H-11/H2-9a/H2-8b, H-11/H2-17b, H2-17b/H2-3a, and H2-3a/H2-4b revealed that these protons were β-oriented. Accordingly, the key NOESY correlations of H2-19a/H2-4a/H2-21a and H2-8a/H-7/H2-18a revealed that C-5, C-6 and C-7 were 5R*, 6R*, 7R* respectively (Fig. 2). Ultimately, the absolute configuration of 3 was identified as 5R, 6R, 7R, 11R by ECD calculations (Fig. 3).

Sophoralopeine A (4) was obtained as colorless oil. Its molecular formula, C16H22N2O, was determined by the HRESIMS (m/z : 259.1809 [M + H]+, calcd. 259.1805). The 1H NMR spectrum of 4 showed a set of AMX spin system of aromatic H atoms (δH 8.40, d, J = 5.0 Hz, H-14; δH 7.39, d, J = 7.8 Hz, H-16; δH 7.09, dd, J = 7.8, 5.0 Hz, H-15), a nitrogenated methine (δH 1.79, m, H-6), and two nitrogenated methenes (δH 3.91, dd, J = 10.9, 5.6 Hz, H2-11a; δH 3.79, dd, J = 10.9, 2.0 Hz, H2-11b; δH 3.15, d, J = 11.8 Hz, H2-2a; δH 1.72, m, H2-2b). The 13C and HSQC spectra displayed resonances for two sp2 quaternary carbons, three sp2 methines, four sp3 methines, and seven sp3 methylenes (Tables S1 and S2). The 1H–1H COSY correlations of H2-2/H2-3/H2-4/H2-5/H-6/H-7/H2-8/H-9/H-10/H2-11, the HMBC correlations of H-2 to C-6 (δC 62.3), together with the chemical shift of C-2 (δC 53.5), C-6 (δC 62.3), and C-11 (δC 64.8) indicated the existence of decahydropyrido[1,2-α ]azepine skeleton (rings A and B) (Figs. 1 and 2) [25]. Moreover, the 1H–1H COSY correlations of H-14/H-15/H-16 and H2-18/H-7/H2-8/H-9, together with the HMBC correlations of H-9 to C-12 (δC 162.3)/C-17 (δC 130.4), of H2-18a to C-16 (δC 138.1)/C-17/C-12, and of H-14 to C-12 indicated the existence of 5,6,7,8-tetrahydroquinoline moiety (rings C and D) (Figs. 1 and 2) [26]. Furthermore, the 1H–1H COSY of H-7/H2-8/H-9, and the HMBC correlation of H-10 to C-12 indicated the above two moieties were connected via the C7–C8–C9 bond. Thus, the unique 6/7/6/6 tetracyclic core have been formed on the basis of the fragments established above.

The NOESY correlations of H2-18b/H-6 and H-6/H-10 indicated that these protons were cofacial and were arbitrarily assigned as β-oriented. Meanwhile, the correlations of H-7/H2-18a, H2-18a/H2-8b, H2-8b/H-9 revealed that H-7 and H-9 were all α-oriented (Fig. 2). Finally, the absolute configuration of 4 (6R, 7R, 9 S, 10 S) was determined by ECD calculations (Fig. 3).

Sophoralopeine B (5) was obtained as colorless oil. Its molecular formula, C17H22N2O, was determined by the HRESIMS (m/z : 271.1802 [M + H]+, calcd. 271.1805). The 1H NMR spectrum of 5 displayed two olefin protons (δH 5.81, d, J = 6.1 Hz, H-10; δH 5.67, d, J = 6.1 Hz, H-17), a nitrogenated methine (δH 4.94, d, J = 3.1 Hz, H-11), and two nitrogenated methenes (δH 3.69, ddd, J = 17.1, 5.7, 4.3 Hz, H2-2a; δH 3.57, ddd, J = 17.1, 7.8, 4.3 Hz, H2-2b; δH 3.43, dd, J = 14.1, 6.9 Hz, H2-13a; δH 2.90, m, H2-13b). The 13C and HSQC spectra displayed resonances for one methyl, seven sp3 methylenes, two sp2 methines, three sp3 methines, and four sp2 quaternary carbons (Tables S1 and S2). The 1H–1H COSY correlations of H2-2/H2-3/H2-4, and H-7/H2-8/H-9/H-10, combined with the HMBC correlations of H-2, H-7, and H2-8 to C-6 (δC 167.1), and of H2-4 to C-5 (δC 128.8)/C-6/C-10 (δC 132.5) indicated the existence of 2,3,4,6,7,8-hexahydroquinoline skeleton (rings A and B) (Figs. 1 and 2) [27]. Meanwhile, the 1H–1H COSY correlations of H-17/H-7/H2-8/H-9/H-11 and H2-13/H2-14/H2-15, together with the HMBC correlations of H-11 to C-13 (δC 42.9)/C-16 (δC 134.4)/C-17 (δC 125.7), of H-17 to C-15 (δC 27.3) indicated the existence of octahydroquinoline moiety (rings C and D) (Figs. 1 and 2) [28]. Furthermore, the 1H–1H COSY H-17/H-7/H2-8/H-9/H-10 indicated the above two moieties were connected via the C7–C8–C9 bond. Thus, the unique 6/6/6/6 tetracyclic core have been formed on the basis of the fragments established above. In addition, the key HMBC correlations of H2-13 to the acetyl group (δC 169.8) demonstrated that the acetoxyl group was connected to N-12 (Fig. 2).

The NOESY correlations of H2-15b/H-11, H-11/H2-8b, and H-9/H2-8b/H-7 indicated that H-7, H-9, and H-11 were α-oriented (Fig. 2). Finally, the absolute configuration of 5 (7R, 9R, 11S) was determined by ECD calculations (Fig. 3).

The biosynthetic pathway for 1–5 are illustrated in Scheme 1. L-Lysine undergoes a series of reactions to yield matrine and aloperine [6,7]. Matrine could be converted to 5,6-dehydro-matrine through oxidation and dehydration, followed by oxidative ring-opening and intramolecular nucleophilic addition to generate the key intermediate alopecuroidine A [20]. On the one hand, alopecuroidine A undergoes ring-opening, C—N bond cleavage, electromigration, and oxidative reaction to generate 1 [29]. On the other hand, alopecuroidine A goes through ring-opening, Michael addition reaction, decarboxylation, and oxidation to yield 2 [30]. Moreover, 5,6-dehydro-matrine undergoes the Michael addition with acetoacetyl-CoA to obtained B1. After cyclizition and reduction, B1 could afford 3 [30]. The key intermediate C2 was derived from aloperine through reduction and oxidative ring-opening [30]. Subsequently, C2 could further generate 4 via S-adenosyl methionine (SAM) catalysed methylation, Michael addition, and reduction [31–33]. In addition, C2 undergoes a cascade of reduction, Michael addition, dehydration, and acetylation to obtain 5 [34].

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Scheme 1. Hypothetical biosynthetic pathways for 1–5.

The anti-TMV activities of 1–5 were evaluated using the half-leaf method (100 mg/L) (Table S3 in Supporting information) [2]. Notably, 5 displayed a significant protective effect and curative effect with concentration for 50% of maximal effect (EC50) values of 19.6 µg/mL (curative), which was superior to that of positive control ningnanmycin (EC50: 54.8 µg/mL) (Table S4 in Supporting information). Moreover, the transcription levels of the TMV Cp and Rdrp genes were detected by quantitative real time polymerase chain reaction (qRT-PCR) in the inoculated and systematic leaves for the in vivo curative and protective assays. Biological tests indicated that compound 5 strongly inhibited the expression of the TMV Cp and Rdrp genes (Fig. 4).

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Fig. 4. The expression levels of TMV Cp and Rdrp genes in inoculated and systematic K326 leaves following treatment with 5 in protective and curative effects. (A) The level of TMV Cp gene expression in inoculated leaves (protective). (B) The level of TMV Cp gene expression in systematic leaves (protective). (C) The level of TMV Cp gene expression in inoculated leaves (curative). (D) The level of TMV Cp gene expression in systematic leaves (curative). (E) The level of TMV Rdrp gene expression in inoculated leaves (protective). (F) The level of TMV Rdrp gene expression in systematic leaves (protective). (G) The level of TMV Rdrp gene expression in inoculated leaves (curative). (H) The level of TMV Rdrp gene expression in systematic leaves (curative). Solution of equal DMSO was used as a negative control agent (CK).

In summary, this study established the structures of five new QAs covering five novel skeletons. Bioactivity evaluations revealed that 5 displayed significant anti-TMV activity than the positive control ningnanmycin. Furthermore, compound 5 could not only inhibit the accumulation of TMV Cp and Rdrp genes but also enhance the host plant's resistance to TMV infection. Therefore, compound 5 can serve as a lead compound for the discovery of new antiviral agents for the management of TMV.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

The work was financially supported by the National Natural Science Foundation of China (Nos. 32160103 and U1812403), the Science and Technology Department of Guizhou Province (Nos. QKH ZC-[2021]-YB181, QKH CXTD-[2022]−007 and QKH ZYD-[2022]−4015), and Guizhou Provincial Engineering Research Center for Natural Drugs.

Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2023.108927.

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