Home Journals Articles Updates About
CN
image
收藏切换
Polycyclic polyprenylated acylphloroglucinol with an unprecedented spirocyclic core from Hypericum patulum
收藏切换
PDF
Yansong Yea, c, 1, Nana Jianga, c, 1, Xianwen Yangb, Gang Xu*, a
Chinese Chemical Letters | 2020, 31(9) : 2433 - 2436
Less
收藏切换
Chinese Chemical Letters | 2020, 31(9): 2433-2436
• Communication •
Polycyclic polyprenylated acylphloroglucinol with an unprecedented spirocyclic core from Hypericum patulum
Full
Yansong Yea, c, 1, Nana Jianga, c, 1, Xianwen Yangb, Gang Xu*, a
Affiliations
  • a State Key Laboratory of Phytochemistry and Plant Resources in West China and Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
  • b Key Laboratory of Marine Biogenetic Resources, Third Institute of Oceanography, Xiamen 361005, China
  • c University of Chinese Academy of Sciences, Beijing 100049, China
Published: 2020-09-15 doi: 10.1016/j.cclet.2020.04.028
Outline
收藏切换

Spirohypatone A (1), a spirocyclic PPAP (polycyclic polyprenylated acylphloroglucinol) bearing an unprecedented hexahydro-1'H-spiro [cyclohexane-1, 2'-pentalene]-2, 4, 6-trione core and a new homologue (spirohypatone B, 2) were isolated from Hypericum patulum together with two known biosynthetic precursors. Compound 1 represents the first spirocyclic PPAP possessing a 5/5/6 carbon ring system, biogenetically derived from the intermediate 3 (attack from C-3 to C-12), which was differed from normal spirocyclic PPAPs (attack from C-3 to C-11). In addition, through extensive spectroscopic analysis, an interconversion mechanism of keto-enol of 1 was postulated and confirmed by its methylated reaction. The structures and absolute configurations of 1 and 2 were determined by comprehensive spectroscopic and chemical derivatized methods and X-ray crystallography. Compounds 1, 2, and 4 were tested to exhibit cytotoxic activities against several cancer cell lines.

Spirocyclic PPAP  /  Hypericum patulum  /  Structural elucidation  /  Derivatives  /  Cytotoxic activities
Yansong Ye, Nana Jiang, Xianwen Yang, Gang Xu. Polycyclic polyprenylated acylphloroglucinol with an unprecedented spirocyclic core from Hypericum patulum[J]. Chinese Chemical Letters, 2020 , 31 (9) : 2433 -2436 . DOI: 10.1016/j.cclet.2020.04.028
Full Text
Less
Polycyclic polyprenylated acylphloroglucinols (PPAPs) with highly oxygenated dearomatized isoprenylated acylphloroglucinol cores represent a special class of secondary metabolites formed by hybridization the mevalonate/methylerythritol phosphate and polyketide biosynthetic pathways [1]. Due to complicated structures and a broad range of biological activities, this type of metabolites has become a hot topic in the research of natural products. Structurally, PPAPs can be divided into bridged-cyclic with bicyclo[3.3.1]nonane-2, 4, 9-trione cores, adamantane, homoadamantane, spirocyclic, and some other complicated architectures according to their different scaffolds [2]. To date, more than 50 spirocyclic PPAPs have been reported and they are mainly share an octahydrospiro[cyclohexan-1, 5-indene]-2, 4, 6-trione 5/6/6 ring system or its seco-cyclic skeletons [2, 3].
Hypericum patulum, a traditional medicinal plant in China, was used for treatment of hepatitis tonsillitis and bruises [4]. Recently, hyperinoids A and B, two PPAPs that showed significant antiinflammatory effects were reported from this plant [5]. Our group has been devoted to the study of bioactive PPAPs from Hypericum and Garcinia genus for a long time and reported a lot of PPAPs with various skeletons such as hypersubone A, hyphenrone A, and garsubelone A [6]. Recently, our team have found a series of PPAPs as the most potent Cav3.1 agonist and antagonist [7]. As part of our ongoing discovery for bioactive PPAPs with novel structures, spirohypatone A (1), a spirocyclic PPAP bearing an unprecedented hexahydro-1'H-spiro[cyclohexane-1, 2'-pentalene]-2, 4, 6-trione core, was characterized from H. patulum together with a new normal spirocyclic PPAP with 5/6/6 ring system (spirohypatone B, 2) and two known biosynthetic precursors (3 and 4) (Fig. 1). Structurally, spirohypatone A (1) represents the first spirocyclic PPAP with a 5/5/6 carbon ring system. It is noteworthy that the NMR spectra of 1 exhibited two sets of signals since the existence of a keto-enol tautomerism. And its structure was determined by the detailed analysis of the high-quality single crystals and clear spectra of the methylated derivatives (1a and 1b). Biosynthetically, 1 could be derived from the key intermediate 3 (attack from C-3 to C-12), which was distinctively differed from normal spirocyclic PPAPs (attack from C-3 to C-11) with 5/6/6 skeleton such as compound 2.
Spirohypatone A (1) was obtained as colorless oil. Its molecular formula, C26H38O5, was established by HRESIMS (m/z 453.2608, [M + Na]+, calcd. 453.2611) indicating 8 degrees of unsaturation (Fig. S8 in Supporting information). The 1D NMR spectra exhibit two sets of signals as a result of tautomerism of keto-enol (Figs. S1 and S2 in Supporting information), which have been reported as a relatively common phenomenon in this type of metabolites [7, 8]. The planar structure of 1 could be elucidated by the major set of NMR data. The 1H NMR spectrum (Table 1) exhibited resonances for one isopropyl group (δH 1.08, d, J = 6.5 Hz; 1.23, d, J = 6.5 Hz; 3.49, sept., J = 6.5 Hz), one olefinic proton (δH 4.57), and six methyl singlets. The 13C and DEPT NMR (Table 2) spectra showed 26 carbon resonances including eight methyls, four methylenes, four methines, and ten quaternary carbons. In particular, a nonconjugated ketone (δC 213.6, C-4), a 1, 3-diketone group (δC 113.7, C-1; 197.7, C-6; 193.4, C-2), two quaternary carbons at δC 78.2 (C-3) and 57.1 (C-5), and a isopropyl group (δC 20.8, C-9; 17.9, C-10; 35.0, C-8) are indicative of characteristic resonances of a disubstituted dearomatized acylphloroglucinol core at C-3 and C-5, respectively [9]. The HMBC correlations from Me-24/25 to C-22/C-23, Me-26/H-21 to C-4/C-5/C-6, together with the 1H–1H COSY correlation of H-21/H-22 confirmed that a methyl and an isoprenyl were attached at C-5 (Fig. 2 and Figs. S3–S5 in Supporting information).
Besides the acylphloroglucinol core and two substituents (a methyl and an isoprenyl) at C-5, the remaining 10 carbons (C-11~C-20) could be a C10 unit derived from two isoprenyls. The planar structure of this C10 unit was deduced by the key 1H-1H COSY correlative interpretations of H-15/H-14/H-13/H-17/H-18 as well as the HMBC correlations from Me-20 to C-15, C-16, and C-17, and from Me-19/11 to C-12 and C-13. Finally, the linkage of acylphloroglucinol and the 10 carbons as shown in Fig. 2 was deduced by the HMBC correlations from Me-11, Me-19 and H2-18 to C-2, C-3 and C-4. Hence, the planar structure of 1 was elucidated to be a spirocyclic PPAP possessing an hexahydro-1'H-spiro [cyclohexane-1, 2'-pentalene]-2, 4, 6-trione core.
Although the planar structure of 1 can be characterized by 1D and 2D NMR data, due to overlapping NMR signals of tautomer, the confirmation of structure is a real challenge. In order to finally determine its structure and absolute configuration without any doubt, the methylated derivatives of 1 (1a and 1b) were prepared with TMS-CHN2 to elucidate its configuration and ensure its correctness of planar structure (Fig. 3). Eventually, high-quality single crystals of 1a were obtained and prepared for X-ray analysis (CCDC: 1990172), which determined the absolute configuration of 1 as 3S, 5R, 13S, 16R, 17S undoubtedly (Fig. 4).
Spirohypatone B (2) was purified as colorless crystals. The molecular formula was determined as C30H44O6 by analysis of its HRESIMS (m/z 523.3033, [M + Na]+, calcd. 523.3030) and 13C NMR data (Fig. S32 in Supporting information and Table 2). The 1H NMR spectrum showed two olefinic proton at δH 4.60 and 4.92, an isopropyl group (δH 1.12, d, J = 7.1 Hz; 1.22, d, J = 7.1 Hz; 3.67, sept, J = 7.1 Hz), and six singlet methyls (Table 1 and Fig. S25 in Supporting information). The 13C NMR and DEPT spectra revealed 30 carbon signals corresponding to two nonconjugated carbonyls at δC 213.3 (C-4) and 209.0 (C-7), a 1, 3-diketone group (δC 111.5, C-1; 196.4, C-6; 195.7, C-2), four sp3 quaternary carbons (two oxygenated ones), two methyls, four methylenes, two methines, and 13 other resonances assignable to an isopropyl and two isoprenyls (Table 2 and Fig. S26 in Supporting information). Analysis of these data indicated the characteristic signals of a spirocyclic PPAP [9, 10]. Detailed comparison of the NMR data of 2 with those of tomoeone A from H. ascyron revealed that they could share the same planar structure [10], which was confirmed by the 1H-1H COSY and HMBC spectra (Fig. 2 and Figs. S27–S29 in Supporting information). However, the different chemical shifts of C-4, C-17, and C-13 in 2 and tomoeone A suggested configurational difference of the two compounds. The NOE cross-peaks of H-17/H-11a/H-13, H-13/Me-19, H-17/Me-20 and H-27/H-11a in the ROESY spectrum (Fig. S30 in Supporting information) indicated that the relative configuration of 2 together with the fact that compound 2 was the C-13 epimer of tomoeone A. Finally, the X-ray crystallography of 2 result (CCDC: 1990149) not only confirmed 2 as epimer of tomoeone A at C-13 but also unambiguously determined its absolute configuration as 3S, 12R, 13S, 16R, 17S (Fig. 4).
Spirohypatone A (1) represent the first example of spirocyclic PPAP with 5/5/6 carbon ring system, which differed from the normal spirocyclic PPAP with 5/6/6 carbon ring skeleton. Biosynthetically, spirocyclic PPAPs could derived from MPAPs (monocyclic polyprenylated acylphloroglucinols) [1, 2]. The geranyl side chain of MPAP may be cyclized to formed chinesin II (3)[11, 12] and hypercalin C (4) [11], which have also been isolated in this study. Thereafter, the 3 undergoes a reaction to produce key intermediate i. Then, the attack from C-3 to C-11 of i form the normal spirocyclic PPAP (2) with the known octahydrospiro [cyclohexan-1, 5-indene]-2, 4, 6-trione architecture, while attack from C-3 to C-12 form 1 with an unprecedented hexahydro-1'Hspiro[cyclohexane-1, 2'-pentalene]-2, 4, 6-trione architecture (Scheme 1).
The cytotoxic effects of these isolates on several cancer cell lines were assayed. Compound 4 was tested to exhibited significant activities against NCI-H460, HCT-15, and MCF-7 cell lines with IC50 values of 1.96, 1.94, and 2.37 μmol/L, respectively. Moreover, 1 and 2 also tested to show weak and moderate cytotoxic effects against HL-60 (the IC50 values of 33.43 for 1 and 16.08 μmol/L for 2) and A549 (IC50 29.5 and 33.55 for 1 and 2, respectively).
In summary, spirohypatone A (1), a PPAP type metabolites bearing an undescribed hexahydro-1'H-spiro[cyclohexane-1, 2'-pentalene]-2, 4, 6-trione core, and a normal spirocyclic PPAP (spirohypatone B, 2) with the known octahydrospiro[cyclohexan-1, 5-indene]-2, 4, 6-trione core were isolated from H. patulum together with their known biosynthetic precursors. Compound 1 represents the first spirocyclic PPAP with 5/5/6 ring system and can be considered as a new type of spirocyclic PPAP. Biosynthetically, although 1 and 2 derived from intermediates with the same skeleton (3 and 4), the C-3 attacks different positions (C-11 and C-12) and eventually leads to produce distinct spirocyclic PPAPs. In the bioactive assay, compounds 1 and 2 were tested to show inhibitory effects on HL-60 and A549, while 4 was found to exhibited significant cytotoxicities against NCI-H460, HCT-15, and MCF-7 cell lines. Altogether, these findings enrich the diversity of structural type of PPAPs.
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
The work was financially supported by the NSFC-Joint Foundation of Yunnan Province (No. U1902213), the Second Tibetan Plateau Scientific Expedition and Research (STEP) Program (No. 2019QZKK0502020303), Southeast Asia Biodiversity Research Institute, CAS (No. 2017CASSEABRIQG003), and the Natural Sciences Foundation of Yunnan Province (No. 2019FA003).
Appendix A. Supplementary data
Less
Supplementary material related to this article canbe found, inthe online version, at doi:https://doi.org/10.1016/j.cclet.2020.04.028.
References
Less
[1]
R. Ciochina, R.B. Grossman, Chem. Rev. 106 (2006) 3963-3986.
[2]
X.W. Yang, R.B. Grossman, G. Xu, Chem. Rev. 118 (2018) 3508-3558.
[3]
(a) Y.T. Duan, J. Zhang, Y.Z. Lao, et al., Tetrahedron Lett. 59 (2018) 4067-4072; (b) Z.N. Wu, Q.W. Niu, Y.B. Zhang, et al., RSC Adv. 9 (2019) 7961-7966; (c) J.J. Zhang, X.W. Yang, J.Z. Ma, et al., Nat. Prod. Bioprospect. 4 (2014) 73-79.
[4]
State Administration of Traditional Chinese Medicine of the People's Republic of China, Chinese Materia Medica, Vol. 9, Shanghai Scientific and Technical Publishers, Shanghai, 1999, pp. 594-608.
[5]
X. Jia, Y. Wu, C. Lei, et al., Chin. Chem. Lett. 31 (2020) 1263-1266.
[6]
(a) Y. Liao, X. Liu, J. Yang, et al., Org. Lett. 17 (2015) 1172-1175; (b) Y.L. Wang, Y.S. Ye, W.W. Fu, et al., Org. Lett. 21 (2019) 1534-1537; (c) X.W. Yang, Y.Q. Ding, J.J. Zhang, et al., Org. Lett. 16 (2014) 2434-2437.
[7]
Y.S. Ye, W.Y. Li, S.Z. Du, et al., J. Med. Chem. 63 (2020) 1709-1716.
[8]
N. Zhang, Z. Shi, Y. Guo, et al., Org. Chem. Front. 6 (2019) 1491-1502.
[9]
(a) S. Abe, N. Tanaka, J. Kobayashi, J. Nat. Prod. 75 (2012) 484-488; (b) S. Yin, X. Chen, Z.S. Su, et al., Tetrahedron 65 (2009) 1147-1152; (c) W. Xin, X. Man, C. Zheng, et al., Fitoterapia 83 (2012) 1540-1547; (d) N. Tanaka, S. Abe, J. Kobayashi, Tetrahedron Lett. 53 (2012) 1507-1510; (e) H. Zhu, C. Chen, J. Liu, et al., Phytochemistry 115 (2015) 222-230.
[10]
W. Hashida, N. Tanaka, Y. Kashiwada, et al., Phytochemistry 69 (2008) 2225-2230.
[11]
L.A. Decosterd, H. Stoeckli-Evans, J.C. Chapuis, B. Sordat, K. Hostettmann, Helv. Chim. Acta 72 (1989) 1833-1845.
[12]
Y. Aramaki, K. Chiba, M. Tada, J. Chem. Soc. Perkin Trans. I 1 (1995) 683-688.
Appendix
Less
Year 2020 volume 31 Issue 9
PDF
35
18
Cite this Article
BibTeX
Article Info
doi: 10.1016/j.cclet.2020.04.028
  • Receive Date：2020-03-15
  • Online Date：2026-01-31
  • Published：2020-09-15
Article Data
Affiliations
History
  • Received：2020-03-15
  • Revised：2020-04-14
  • Accepted：2020-04-15
Affiliations
    a State Key Laboratory of Phytochemistry and Plant Resources in West China and Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
    b Key Laboratory of Marine Biogenetic Resources, Third Institute of Oceanography, Xiamen 361005, China
    c University of Chinese Academy of Sciences, Beijing 100049, China
References
Share
https://castjournals.cast.org.cn/joweb/ccl/EN/10.1016/j.cclet.2020.04.028
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