Home Journals Articles Updates About
CN
image
收藏切换
Mufolinin A, an unprecedented ring A-seco 10-ethyllimonoid from Munronia unifoliolata
收藏切换
PDF
Yunpeng Sun, Letian Cui, Qiurong Li, Pengfei Tang, Yongyi Li, Wenjun Xu, Jun Luo*, Lingyi Kong*
Chinese Chemical Letters | 2022, 33(1) : 516 - 518
Less
收藏切换
Chinese Chemical Letters | 2022, 33(1): 516-518
• Communication •
Mufolinin A, an unprecedented ring A-seco 10-ethyllimonoid from Munronia unifoliolata
Full
Yunpeng Sun, Letian Cui, Qiurong Li, Pengfei Tang, Yongyi Li, Wenjun Xu, Jun Luo*, Lingyi Kong*
Affiliations
  • Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
Published: 2022-01-15 doi: 10.1016/j.cclet.2021.06.050
Outline
收藏切换

Mufolinin A (1), a ring A-seco rearranged limonoid with an unprecedented ethyl at C-10 and novel 6/6/6/5 fused-ring skeleton, together with three new potential precursors (ring A-seco limonoids, 2–4) were isolated from Munronia unifoliolata. Their structures and absolute configurations were confirmed by nuclear magnetic resonance (NMR), high resolution electrospray ionization mass spectroscopy (HRESIMS), X-ray crystallography, electronic circular dichroism (ECD) calculations and NMR calculations with DP4+ analyses. The unprecedented ethyl group of 1 was hypothesized to be derived from methyl migration and ring reduction rearrangement of ring A-seco limonoid 4. Compounds 2 and 4 showed significant multidrug resistance (MDR) reversal activities in MCF-7/DOX cells with reversal fold (RF) values of 13.1 and 8.0, respectively.

Meliaceae  /  Munronia unifoliolata  /  Limonoids  /  Anti-inflammatory  /  Anti-multidrug resistance
Yunpeng Sun, Letian Cui, Qiurong Li, Pengfei Tang, Yongyi Li, Wenjun Xu, Jun Luo, Lingyi Kong. Mufolinin A, an unprecedented ring A-seco 10-ethyllimonoid from Munronia unifoliolata[J]. Chinese Chemical Letters, 2022 , 33 (1) : 516 -518 . DOI: 10.1016/j.cclet.2021.06.050
Full Text
Less
Limonoids are a class of natural products with diverse skeleton types and a wide spectrum of biological activities, widely distributed in the plants of Meliaceae and Rutaceae. Simple ring-intact limonoids with 17β-furan ring are formed by loss of four-terminal carbons of the side chain in the apotirucallane or apoeuphane skeleton [1]. Under the action of the enzyme, the ring-intact limonoids with tetracyclic skeleton can undergo oxidation and ring opening to form a variety of ring-seco limonoids [2]. Further oxidative rearrangement allows diverse structure types of limonoids to be possible [3]. In previous studies, we reported several kinds of novel limonoid skeletons with ring cleavage and carbon skeleton rearrangement [4]. To our knowledge, the formation of a novel limonoid skeleton via methyl migration is very rare, only one 18(13→14)-abeo-limonoid skeleton has been reported [5].
The plants from Munronia genus (Meliaceae) are dwarf shrubs or semi shrubs, and some of them have been used as traditional Chinese medicine ("Aituotuo" in Chinese) for treatment of bruises, rheumatic joint pains, coughs, stomach-aches, tuberculosis and sores [6]. In recent years, more than 60 ring-intact and ring-seco limonoids with significant anti-inflammatory, antimicrobial and anti-tobacco mosaic virus (TMV) biological activities have been isolated from "Aituotuo" [7]. M. unifoliolata, one of the resources of "Aituotuo", is widely distributed in the southwest of China and also contains abundant limonoids [8]. In this research, an A-ring rearranged limonoid with an unprecedented ethyl at C-10 and novel 6/6/6/5 fused-ring skeleton, mufolinin A (1), together with three new potential precursors (ring A-seco limonoids, 2–4) (Fig. 1) were isolated from the whole plant of M. unifoliolata. Their structures were elucidated on the basis of extensive one dimension (1D) and two dimension nuclear magnetic resonance (2D NMR) experiments, X-ray crystallographic method, electronic circular dichroism (ECD) calculations and NMR calculations with DP4+ analyses. Based on the traditional medicinal efficacy of M. unifoliolata, bioactivities including anti-inflammatory and anti-MDR activities of compounds 1–4 were also tested. Herein, the details of the isolation, structure elucidation, biosynthetic relationship and bioactivities of mufolinins A–D (1–4) were described.
Mufolinin A (1) was obtained as white amorphous powder. Its high resolution electrospray ionization mass spectroscopy (HRESIMS) displayed a quasi-molecular ion peak at m/z 549.2457 [M + Na]+, corresponding to the molecular formula C30H38O8 with 12 degrees of unsaturation. The 1H and 13C NMR spectra (Table S1.1 in Supporting information) indicated that 1 was a ring A-seco limonoid, and its B, C and D rings with Δ9, 11 and Δ14, 15 double bonds were readily established by comparison with those of several known limonoids [8] and key heteronuclear multiple bond correlations (HMBCs) (Fig. 2). Surprisingly, the 1H NMR spectrum (Fig. S4.1.1 in Supporting information) exhibited a secondary methyl group (δH 1.35), which showed 1H–1H coupling correlation spectroscopy (COSY) correlation to H-1 (δH 4.97) and the HMBC cross-peaks to C-1 (δC 76.0) and C-10 (δC 46.1). These data indicated that an acetyl-substituted ethyl group was connected to C-10, which was also confirmed by the HMBC correlations from H-1 to C-9 (δC 138.9), C-10 (δC 46.1), C-2 (δC 42.3), C-5 (δC 47.8) and a carbonyl carbon (δC 170.1). Meanwhile, the heptonolactone ring in the general ring A-seco limonoids was reduced into a hexonolactone ring in 1, which was further confirmed by the HMBC correlations from H-2 (δH 2.79 and 2.64) to C-3 (δC 171.0), C-5, and from H3-28 (δH 1.62) to C-3. Thus, the unprecedented C-10 ethyl and novel 6/6/6/5 fused-ring skeleton of 1 were assigned.
The relative configuration of 1 was established by analysis of its rotating-frame overhauser spectroscopy (ROESY) spectrum (Fig. 2). The ROESY correlations of H3-19 and H-1 to H-5 suggested a same orientation of these protons which were assigned to be α-oriented. Meanwhile, the correlations of H3-19/H3-18/H-12 (δH 2.40) and H-1/H3-28 determined the spatial orientation of the ethyl group. The β-orientation of H-6, H-7, H-17, H3-29 and H3-30 were confirmed by the ROESY correlations of H3-30/H-7/H-6/H3-29, and H-17/H-12 (δH 2.11) (Fig. S4.1.6 in Supporting information). To determine the configuration of C-1, the 13C chemical shifts of two tentative C-1 epimers (1R)-1 and (1S)-1 were calculated by the density functional theory (DFT) gage independent atomic orbital (GIAO) method at the mPW1PW91/6–311+G(d, p) theory level (Fig. S1.1 in Supporting information) [9]. Further DP4+ analyses based on both 1H and 13C NMR data indicated (1S)-1 as the correct structure with 100% probability [10]. Finally, the absolute configuration of 1 (1S, 5S, 6R, 7S, 8S, 10S, 17R) was confirmed by comparing the experimental and calculated ECD data with time-dependent density functional theory (TD-DFT) (Fig. S1.3 in Supporting information). Hence, the novel structure of 1 was depicted as shown in Fig. 1.
The 1D NMR data (Table S1.1 in Supporting information) of mufolinins B (2) and C (3) showed characteristic signals of a β-substituted furan ring, an α, β-unsaturated lactone group, and at least one acetoxy substituent in each compound, making them structurally similar to munronoid D [8a], a ring A-seco limonoid with a 3, 4-lactone. Compared 2 with munronoid D, the only difference was a β-substituted furan ring group (δH 7.37, 7.23, 6.26; δC 142.8, 139.9, 111.1, 124.4) at C-17 in 2 instead of a γ-lactone ring. The relative configuration of 2 was corroborated by the ROESY spectrum (Fig. S4.2.6 in Supporting information), in which the correlations of H-6/H-7/H3-30 and H-17/H-12 (δH 1.77) revealed that these protons were on the same side as β-orientation. The ROESY cross-peaks of H-5/H-9/H3-18/H-12 (δH 1.85) indicated that H-5, H-9, H3-18 and H-12 (δH 1.85) were α-oriented (Fig. S1.4 in Supporting information). Mufolinin C (3) gave a molecular formula of C28H36O6, as determined from its HRESIMS ion at m/z 491.2406 [M + Na]+ (calcd. 491.2404), which exhibited 42 daltons less than that of 2. In NMR spectroscopic data of 3 and 2, the observed significant upfield shifts of H-6 (δH 4.28, Δδ −1.03) and C-6 (δC 67.6, Δδ −2.4) indicated replacement of the acetoxy group at C-6 in 2 by a hydroxy group in 3. Based on 1D NMR data and ROESY correlations, the relative configuration of 3 was assigned to be the same as that of 2 (Fig. S1.4 in Supporting information). Therefore, the structures of 2 and 3 were established as shown in Fig. 1.
Mufolinin D (4) was obtained as colorless crystals. It was assigned the molecular formula of C30H40O8, as established by HRESIMS. The 1D NMR data (Table S1.1 in Supporting information) of 4 showed many similarities to those of 3, with the main differences in the absence of a Δ1, 2 double bond and the presence of an acetoxy group in 4. The above changes were established by analysis of HMBC correlations from H-1 (δH 4.86) to C-5 (δC 48.3), Me-19 (δC 17.4) and the acetoxy carbonyl (δC 169.1), and the 1H–1H COSY cross-peak of H-1/H-2 (δH 2.64, 2.96) in 4 (Fig. S1.4 in Supporting information). The relative configuration of 1-OAc was assigned as α-oriented by the ROESY correlations of H-1/H3-19 and H-1/H3-30. Moreover, a single-crystal X-ray diffraction experiment (Fig. S1.5 in Supporting information) allowed the full assignment of the absolute configuration of 4 (1S, 5S, 6R, 7S, 8R, 9R, 10R, 13S, 17R) [Flack parameter = 0.05(6); CCDC 2013523].
The hypothetical biosynthetic pathway of 1 was illustrated in Scheme 1. Abundant ring A-seco limonoids, such as mufolinin D (4) isolated, were considered to be the precursor. Compound 4 was deacetylated to give 3 with Δ1, 2 double bond and then oxidized continuously to obtain 1, 2 epoxide Ⅰ with double bond C-9/11 under the action of the enzyme. Subsequently, nucleophilic attack from AcO− to 1, 2-epoxy formed the intermediate Ⅱ. The hydroxy group left under acidic conditions to form a carbocation, triggering Wagner-Meerwein rearrangement. As a result, Me-19 migrated to C-1, and a rearranged carbocation (C-10) was generated. Subsequently, the loss of a proton delivered the double bond C-5/10 [5a]. The acetoxy group at the ortho position of the ester carbonyl group led to the formation of a free radical [11], which then reacted with the double bond in the ring and produced a three-membered ring. Finally, under the nucleophilic attack of AcO−, the three-membered ring with high tension underwent ring opening process to afford compound 1.
Mufolinins A–D (1–4) were tested for their inhibitory effects on nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells [12] and the reversal activities of multidrug resistance (MDR) in MCF-7/DOX cells. Compound 2 exhibited moderate anti-inflammatory activity with the half maximal inhibitory concentration (IC50) value of 31.2 µmol/L (NG-monomethyl-l-arginine monoacetate was used as a positive control with the IC50 value of 44.4 µmol/L). Moreover, 2 and 4 at the concentration of 10 µmol/L showed significant MDR reversal effects on MCF-7/DOX cells subjected to doxorubicin (DOX), of which compound 2 was even better than the positive drug verapamil (Table 1).
In conclusion, mufolinin A (1), the first example of ring A rearranged limonoid with unprecedented ethyl at C-10 and novel 6/6/6/5 fused-ring skeleton, was isolated from M. unifoliolata, together with three possible biosynthetic precursors mufolinins B–D (2–4). This is the first report of limonoid undergoing methyl migration and ring reduction rearrangement. In addition, compounds 2 and 4 showed significant multidrug resistance (MDR) reversal activities in MCF-7/DOX cells, which was similar to or even better than the positive control verapamil at the same dosage. This research provided a reference for the study of novel limonoids and their pharmacological activities from M. unifoliolata.
Declaration of competing interest
Less
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
Less
This work was supported by the National Natural Science Foundation of China (No. 31470416), the 111 Project from Ministry of Education of China and the State Administration of Foreign Export Affairs of China (No. B18056). Computational resources used in this work were supported in part by SciGrid, Chinese Academy of Sciences.
Appendix A. Supplementary materials
Less
Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2021.06.050
References
Less
[1]
Q.G. Tan, X.D. Luo., Chem. Rev.111 (2011) 7437–7522.
[2]
(a) P.P. Zhang, Z.R. Cui, S.S. Wei, et al., Ind. Crop. Prod. 148 (2020) 112275; (b) G.L. Zhu, L.S. Wan, X.R. Peng, et al., J. Nat. Prod. 82 (2019) 2419–2429.
[3]
(a) B.J. Yang, S.R. Fan, J.Y. Cai, et al., J. Org. Chem. 85 (2020) 8597–8602; (b) M.L. Bellone, C.M. Camero, M.G. Chini, et al., J. Nat. Prod. 84 (2021) 724–737; (c) W.S. Li, J. Wu, J. Li, et al., Org. Lett. 19 (2017) 182–185.
[4]
(a) J. Luo, W.S. Huang, S.M. Hu, et al., Org. Chem. Front. 4 (2017) 2417–2421;(b) F.L. An, D.M. Sun, R.J. Li, et al., Org. Lett. 19 (2017) 4568–4571;(c) F.L. An, J. Luo, R.J. Li, et al., Org. Lett. 18 (2016) 1924–1927.
[5]
(a) S. Yin, X.N. Wang, C.Q. Fan, et al., Org. Lett. 9 (2007) 2353–2356;(b) B. Zhou, Y. Shen, Y. Wu, et al., J. Nat. Prod. 78 (2015) 2116–2122.
[6]
M.H. Huang, Y.M. Zhang, J. Li, et al., Chin. Tradit. Herbal. Drugs48 (2017) 1240–1249.
[7]
(a) Y. Yan, C.M. Yuan, Y.T. Di, et al., Fitoterapia107 (2015) 29–35;(b) Y. Yan, J.X. Zhang, T. Huang, et al., J. Nat. Prod. 78 (2015) 811–821;(c) B.D. Lin, H.D. Chen, J. Liu, et al., Phytochemistry71 (2010) 1596–1601.
[8]
(a) Y.H. Ge, J.X. Zhang, S.Z. Mu, et al., Tetrahedron68 (2012) 566–572;(b) Y.H. Ge, K.X. Liu, J.X. Zhang, et al., J. Agric. Food. Chem. 60 (2012) 4289–4295.
[9]
M.W. Lodewyk, M.R. Siebert, D.J. Tantillo., Chem. Rev. 112 (2012) 1839–1862.
[10]
N. Grimblat, M.M. Zanardi, A.M. Sarotti., J. Org. Chem. 80 (2015) 12526–12534.
[11]
E.J. Enholm, S.J. Jiang, K. Abboud., J. Org. Chem. 58 (1993) 4061–4069.
[12]
Y. Wang, J. Lin, Q. Wang, et al., Chin. J. Nat. Med. 17 (2019) 953–962.
Appendix
Less
Year 2022 volume 33 Issue 1
PDF
55
31
Cite this Article
BibTeX
Article Info
doi: 10.1016/j.cclet.2021.06.050
  • Receive Date：2021-05-08
  • Online Date：2025-12-12
  • Published：2022-01-15
Article Data
Affiliations
History
  • Received：2021-05-08
  • Revised：2021-06-08
  • Accepted：2021-06-18
Affiliations
    Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
References
Share
https://castjournals.cast.org.cn/joweb/ccl/EN/10.1016/j.cclet.2021.06.050
Share to
QR

Scan QR to access full text

Cite this article
BibTeX
Citations
表12种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
关闭全屏
  • BibTeX
  • EndNote
  • RefWorks
  • TxT
Links
Articles
Latest Articles
Most Read
Collections
Updates
Events
News
Multimedia
About
About Us
Contact
No. 86 Xueyuan South Road, Haidian District, Beijing
100081
010-62199257
qkjq@cast.org.cn

Copyright © 2025 China Association for Science and Technology. All rights reserved. For all open access content, the relevant licensing terms apply.
Sponsored by the Office of the Leading Group for Cybersecurity and Informatization of CAST, and supported by Science and Technology Review Publishing House