Antiviral spirooliganones C and D with a unique spiro[bicyclo[2.2.2]octane-2, 2′-bicyclo[3.1.0]hexane] carbon skeleton from the roots of <i>Illicium oligandrum</i>

Antiviral spirooliganones C and D with a unique spiro[bicyclo[2.2.2]octane-2, 2′-bicyclo[3.1.0]hexane] carbon skeleton from the roots of Illicium oligandrum

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Shuanggang Ma^a^,¹^,^*, Rubing Wang^a^,¹, Rongmei Gao^b, Xiaojing Wang^a, Yunbao Liu^a, Yong Li^a, Li Li^a, Yuhuan Li^b, Jing Qu^a^,^*, Shishan Yu^a^,^*

Chinese Chemical Letters | 2022, 33(9) : 4248 - 4252

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Chinese Chemical Letters | 2022, 33(9): 4248-4252

• Communication •

Antiviral spirooliganones C and D with a unique spiro[bicyclo[2.2.2]octane-2, 2′-bicyclo[3.1.0]hexane] carbon skeleton from the roots of Illicium oligandrum

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Shuanggang Ma^a^,¹^,^*, Rubing Wang^a^,¹, Rongmei Gao^b, Xiaojing Wang^a, Yunbao Liu^a, Yong Li^a, Li Li^a, Yuhuan Li^b, Jing Qu^a^,^*, Shishan Yu^a^,^*

Affiliations

^a State Key Laboratory of Bioactive Sub stance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China

^b Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China

Published: 2022-09-15 doi: 10.1016/j.cclet.2022.02.050

Outline

Abstract

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Two unprecedented polycyclic spirooliganones C and D (1 and 2) with a novel spiro[bicyclo[2.2.2]octane-2, 2′-bicyclo[3.1.0]hexane] carbon skeleton, one known dimeric prenylated C₆C₃ compound (3), and a pair of new enantiomeric prenylated C₆C₃ compounds (+)-5 and (−)-5 together with their direct precursors (+)-4 and (−)-4 were isolated from the roots of Illicium oligandrum. Their structures and absolute configurations were elucidated by spectroscopic analysis, single crystal X-ray diffraction data, and electronic circular dichroism calculations. A possible biosynthetic pathway for compounds 1 and 2 involving the Diels-Alder reaction between (−)-sabinene and cyclic prenylated tetrahydropyrano-type C₆C₃ compounds was proposed. The characteristic prenylated C₆C₃ compounds (+)-4 and (−)-4 were separated on a chiral stationary phase and their absolute configurations were determined by calculated ECD for the first time. In the antiviral bioassays, compounds 1 and (+)-5 exhibited significant inhibitory activity against CVB3 with IC₅₀ values of 11.11 µmol/L and 1.11 µmol/L, respectively. Compounds 1 and 2 also showed moderate inhibition against influenza A (H1N1) virus.

Key words

Illicium / Illicium oligandrum / Spirooliganone / Prenylated C₆-C₃ compound / Antiviral activity

Cite this Article

Shuanggang Ma, Rubing Wang, Rongmei Gao, Xiaojing Wang, Yunbao Liu, Yong Li, Li Li, Yuhuan Li, Jing Qu, Shishan Yu. Antiviral spirooliganones C and D with a unique spiro[bicyclo[2.2.2]octane-2, 2′-bicyclo[3.1.0]hexane] carbon skeleton from the roots of Illicium oligandrum[J]. Chinese Chemical Letters, 2022 , 33 (9) : 4248 -4252 . DOI: 10.1016/j.cclet.2022.02.050

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Many infections in humans and animals are caused by RNA viruses, including Coxsackie viruses, which are important human pathogens. Coxsackie viruses belong to the genus Enterovirus (Picornaviridae) and are divided into subgroups A and B based on their pathological effects on newborn mice. Coxsackie virus B3 (CVB3) has been reported to induce acute and chronic viral myocarditis in children and young adults, which is associated with aseptic meningitis, hepatitis, and meningoencephalitis [1]. and chronic dilated cardiomyopathy [2]. Due to the lack of approved antiviral drugs and vaccines for Coxsackie viral infections, there is an urgent need for new antiviral agents.

Plants continue to be an extraordinary reservoir of novel molecules of medicinal value, including the discovery of antivirals. Among the 61 antiviral small-molecule drugs approved from 1981 to 2019, 26 of them are synthetic drugs with natural product pharmacophones and 6 of them are derived from natural products [3], including 3 anti-influenza drugs derived from shikimic acid [4, 5], which was first isolated in 1885 from Illicium religiosum [6, 7]. As a rich source for bioactive natural products, a number of antiviral diterpenes [8, 9], sesquiterpenes [10, 11], and prenylated C₆_nullC₃ compounds [12] have been isolated from plants of the Illicium genus. In particular, prenylated C₆_nullC₃ compounds have always been a notable research topic in the field of natural products and synthetic chemistry due to their complex structures, diverse biological activities, and synthetic challenges [13-19]. Equally notable is that natural products in dimerization patterns biosynthetically derived from Diels-Alder cycloaddition have been increasingly attracted the attention of scientists due to their complex skeletons, biological activities, biosynthetic pathways and synthetic challenges [20-26]. We recently reported the isolation and antiviral activities of some structurally diverse prenylated C₆—C₃ compounds and their complex Diels-Alder adducts with monoterpene or sesquiterpenes from I. oligandrum [19, 27, 28]. Herein, as a part of an investigation into the bioactive compounds from Chinese Illicium plants, the phytochemicals in the ethanol extract of I. oligandrum were explored. Two unprecedented polycyclic spirooliganones C and D (1 and 2) (Fig. 1) were isolated from the roots of I. oligandrum, which features a novel spiro[bicyclo[2.2.2]octane-2, 2′-bicyclo[3.1.0]hexane] carbon skeleton. We also purified and structurally characterized a pair of new enantiomeric prenylated C₆—C₃ compounds (+)-5 and (−)-5, together with their direct precursors (+)-4 and (−)-4. Moreover, illicidione D (3) and compound 4 were identified by comparing their spectroscopic data with previous literature data [29, 30]. The structural elucidation of the new compounds 1, 2, and 5, the absolute configurations of (+)-4 and (−)-4, and the antiviral activity evaluation of all compounds are described herein.

Spirooliganone C (1) was obtained as a crystal. Its molecular formula was deduced to be C₂₄H₃₄O₄ by HRESIMS and NMR (Table 1) data, suggesting 8° of unsaturation. The IR spectrum of 1 displayed characteristic absorbances for hydroxyl (3307 cm⁻¹) and carbonyl (1721 cm⁻¹) functionalities. The ¹³C NMR and DEPT spectra showed 24 resonances attributable to four methyls, seven methylenes (one sp² carbon at δ_C 118.3), six methines (one sp² carbon at δ_C 135.0), six quaternary carbons (two sp² carbons at δ_C 107.3 and 146.3), and one ketone carbonyl at δ_C 210.1. The aforementioned four sp² carbons and a carbonyl accounted for 3° of unsaturation; thus, the remaining 5° of unsaturation required spirooliganone C (1) to possess a pentacyclic skeleton.

In the ¹H NMR spectrum (acetone-d₆), one doublet at δ_H 4.12 (1H, J = 5.5 Hz) and one singlet at δ_H 3.97, which did not display any correlations in the HSQC spectrum, were assignable to the exchangeable protons of two hydroxyls. The ¹H NMR spectrum of 1 also displayed two methyl singlets at δ_H 1.18 and 1.29 and a singlet at δ_H 2.50, which correlated with an intense ¹³C signal at δ_C 60.6 in the HSQC spectrum. The remaining multiplet signals in the ¹H NMR spectrum belonged to six discrete spin systems, a (C7–C9), b (C10–C11), c (C3–C15), d (C17–C18), e (C20–C21), and f (C22–C24) (drawn with thick blue bonds in Fig. 2), as concluded from ¹H–¹H correlation spectroscopy (COSY) and HSQC analysis.

In the HMBC spectrum, correlations (Fig. 2) were observed from H-3 and H-6 to C-1, C-2, C-4, and C-5; from H-3 to C-16; from H-6 to C-15; and from H₂-15 to C-2, C-3, C-4, C-6, and C-16, which indicated that C1-C6, C15-C16, and fragment c constitute a bicyclo[2.2.2]oct–5-en-2-one moiety. The HMBC correlations from H-17 to C-16 and C-20; from H₂-18 to C-19; from H₂-20 to C-18 and C-19; and from H₂-21 to C-16, C-17, C-19, and C-20, as well as the aforementioned two fragments d and e, allowed for the establishment of a bicyclo[3.1.0]hexane moiety. Furthermore, key HMBC correlations from both H-17 and H₂-21 to C-6 and from H₂-15 to C-16 and C-17 were observed and suggested that the bicyclo[2.2.2]oct–5-en-2-one moiety and the bicyclo[3.1.0]hexane moiety were connected through a spirocarbon C-16, constructing an unprecedented carbon skeleton for 1. Additionally, the allyl group (fragment a) and one hydroxyl group were connected to a quaternary C-2 carbon (δ_C 75.0) by means of HMBC correlations from H₂-7 and 2–hydroxyl protons (δ_H 3.97) to C-1, C-2, and C-3. The isopropyl group (fragment f) was connected with C-20 based upon HMBC correlations from H-22 to C-18, C-19, and C-20.

The remaining 5 carbon resonances, including two geminal methyl carbons, indicated the presence of a prenyl unit (C10–C14), as evidenced by HMBC correlations from H₃-13 and H₃-14 to C-11 (δ_C 78.6) and C-12 (δ_C 70.8) and the above-mentioned fragment b. The remaining one degree of unsaturation and the HMBC correlations from H₂-10 to C-3, C-4, and C-5 (an oxygenated sp² carbon) indicated that the prenyl unit in a dihydropyran ring system was fused to the allylated 3-cyclohexenone moiety (a C₆–C₃ unit, C1–C9) at C-4 and C-5. Another hydroxyl group was attached at C-11 by the HMBC correlations from 11–hydroxyl protons (δ_H 4.12) to C-10, C-11, and C-12.

The relative configurations of the seven chiral centers, including one spirocarbon present in the structure of 1, were assigned by employing nuclear Overhauser effect (NOE) and ROESY experiments (Fig. 3). NOEs were observed for Ha-10 and H₃-13 after irradiation of Hb-7 (δ_H 2.27), indicating that the allyl group, Ha-10, and Me-13 were on the same face of the dihydropyranocy-clohexaenone (DHPC) pseudoplane, as depicted in Fig. 2. When Hb-10 was irradiated, strong NOEs for H-11, weak NOEs for 11–hydroxyl protons, and obvious NOEs for Me-14 were observed (Fig. S10 in Supporting information). Similarly, strong NOEs for H-11, weak NOEs for 11–hydroxyl protons, and obvious NOEs for Hb-10 were observed after irradiation with Me-14 (Fig. S10). These data and the ROESY cross peaks of Hb-10/H₃-14 suggested that Hb-10 and Me-14 were on the same face of DHPC and the α-orientation for 11–hydroxyl. On the other hand, the stereochemistry of the spirocarbon in the molecule was also unambiguously assigned by NOE experiments. Diagnostic NOEs for 2–hydroxyl protons, H-3, and Hb-21 were observed after irradiation with H-15a (δ_H 1.98). Moreover, irradiation with H-17 enhanced the signals for Me-14, Hb-15, and Hb-18. These results indicated that the three-member ring in the bicyclo[3.1.0]hexane moiety and Hb-15 were on the same side of the vertical surface formed by C3-C15-C16-C6 and that the three-member ring and CH₂-15 were on the same side of the five-membered ring (C16-C17-C19-C20-C21). Furthermore, the observed NOEs for Hb-15, Hb-20, and Hb-21 after irradiation of H-18a and NOEs for H-22 and H-17 after irradiation of H-18b demonstrated that the isopropyl group and H-17 were on another side of the five-membered ring, opposite the three-membered ring and CH₂-15, as depicted in Fig. 3.

As in bicyclo[2, 2, 2]oct–5-en-2-one, the orientation of the β, γ-unsaturated carbonyl moiety determines the sign of the Cotton effect. The CD spectrum of 1 shows a negative Cotton effect at 318 nm for the n→π* transition of the β, γ-unsaturated carbonyl moiety. Based on the extended octant rule [31, 32] and the aforementioned relative configuration, the absolute stereochemistries of all the stereogenic centers in 1 were determined to be 2R, 3R, 6S, 11R, 16S, 17R, and 19S, which were also supported by the calculated CD spectrum (Fig. 4). It was noted that 1 and its spirocarbon epimer 2 could not be separated by reversed-phase C18 column chromatography, but their separation was achieved on an AD-H chiral column using n-hexane-isopropanol as the mobile solvent. Fortunately, single crystals of 1 were obtained in acetone-H₂O containing residual isopropanol. A single-crystal X-ray diffraction experiment of 1 was performed by using Cu Kα radiation, and the X-ray crystallography data indicated that one molecule of 1 and one isopropanol molecule coexisted in a crystal lattice in the ratio of 1:1, as shown in the stacking diagram (Fig. 5). The refinement of Flack's parameter [0.01(19)] further corroborated the absolute configuration of 1 [33, 34].

Spirooliganone D (2), obtained as a colorless oil, had a molecular formula of C₂₄H₃₄O₄ as deduced from HRESIMS and NMR data (Table 1), which was the same as 1. The ¹H and ¹³C NMR data were very similar between 1 and 2. The correlations observed in the COSY and HMBC spectra were also nearly identical between 1 and 2, suggesting that the same carbon-carbon skeleton is present in 1 and 2. The most substantive differences between these compounds are the NMR data for C-15 and the bicyclo[3.1.0]hexane moiety, indicating that the bicyclo[3.1.0]hexane moiety located at the spirocarbon (C-16) in 2 had the opposite orientation, as depicted in Fig. 3. In NOE experiments, when H-15a was irradiated, diagnostic NOEs for 2–hydroxyl protons, H-17, and H₃-23 were observed. These results suggested that the three-membered ring in the bicyclo[3.1.0]hexane moiety and Ha-15 were on the same side of the vertical surface formed by C3-C15-C16-C16 in 2 and that isopropyl, CH₂-15 and H-17 were on the same side of the five-membered ring (C16-C17-C19-C20-C21), as shown in Fig. 2. The relative configurations of the remaining chair carbons were determined by a series of NOE and ROESY experiments, which resulted in the same configuration as that of the corresponding chair carbons in 1. Moreover, the CD spectrum of 2 had a high degree of similarity to that of 1 (Fig. S21 in Supporting information). Thus, the absolute configuration of 2 was determined to be 2R, 3R, 6S, 11R, 16R, 17R, and 19S.

Biogenetically spirooliganones C-D (1 and 2), a pair of spirocarbon epimers, are the first hybrid examples of monoterpene (−)-sabinene and cyclic prenylated tetrahydropyrano-type C₆—C₃ compounds, compared with the previously reported hetero Diels-Alder adducts spirooliganones A and B formed by (−)-sabinene and spirocyclic prenylated tetrahydrofurano-type C₆—C₃ derivatives. Compounds 1 and 2 share a novelspiro[bicyclo[2.2.2]octane-2, 2′-bicyclo[3.1.0]hexane] 6/6/5/3 tetracyclic ring carbon skeleton. A plausible biosynthetic pathway for 1 and 2 is illustrated in Scheme 1. 4-Allylresorcinol derivatized from phenylalanine [30] can be proposed as the precursor of cyclic prenylated tetrahydropyrano-type C₆—C₃ compound derivatives (vi). Initially, the presumed precursor 4-allylresorcinol undergoes prenylation, 1, 3-σ migration [35] of prenyl, and oxidation steps, followed by key epoxyprenyl side chain cyclization and dehydration to afford intermediate iv. Subsequently, iv would be converted to active diene vi via aromatization-dearomatization [36], followed by a selective Diels-Alder reaction with (−)-sabinene from the direction of small steric hindrance to form a pair of [4 + 2] cycloaddition adducts 1 and 2.

(±)-2-Allyl-2-(3-methylbut-2-enyl)-4, 5-methylenedioxy-cyclo-hexa-3, 5-dienone (4) was isolated as a light yellow oil from the roots of I. oligandrum in a previous investigation [30], which also occurred in plants in the Illicium genus, including I. verum [37], I. burmanicum [38], I. henryi [39], and I. simonsii [40]. This compound was first obtained from 2-allyl-4, 5-methylenedioxyphol by chemical reaction in 1983 [41]. However, only the planar structure of 4 was documented, and the absolute configuration of the chair center in 4 has not yet been resolved. The baseline ECD curve and the low specific rotation showed that 4 was a racemate. Compounds (+)-4 and (−)-4 were separated on a chiral-phase column (Fig. S22 in Supporting information), and the theoretical calculation of ECD spectra of (2S)-4 and (2R)-4 was performed in methanol using the time-dependent density functional theory (TD-DFT) method at the B3LYP/6-311⁺⁺G(d, p) level [42] and compared with the experimental spectra to determine the absolute configuration in 4. As shown in Fig. 6, the calculated ECD curve of 2S matched the experimental ECD curve of (+)-4, and 2R matched the (−)-4 ECD curve with good agreement. Thus, the absolute configurations of (+)-4 and (−)-4 were determined to be 2S and 2R, respectively. Moreover, the (2S) absolute configuration of illioliganone C [43], a dihydroxylated derivative previously isolated from the stem bark of I. oligandrum, was revised to 2R on the basis of a comparison between the experimental ECD spectra of (−)-4 and illioliganone C.

(±)-Illioliganone J (5) was isolated as a colorless oil with [α]₂₀^D = 0 (c 0.05, MeOH). The IR spectrum provided evidence for the carbonyl (1719 and 1632 cm⁻¹) and phenyl (1413 cm⁻¹) groups. From the ESIHRMS spectrum, the identification of a sodium adduct ion at m/z 389.1382 [M + Na]⁺ allowed for us to infer a molecular formula of C₂₂H₂₂O₅ (calcd. for C₂₂H₂₂O₅Na, 389.1365), along with a degree of unsaturation of 12. The ¹H and ¹³C NMR data (Table 2) of 5 closely resembled those of illioliganone D [30], which indicated that they shared the same carbon skeleton of a noncyclic prenylated C₆–C₃ compound. Nevertheless, a detailed comparison of their 1D NMR data revealed that the main differences were the presence of carbon resonances for one methyl group at δ_C 21.7 and one oxygenated methylene group at δ_C 63.9 in illioliganone D, which were replaced by δ_C 14.3 and 70.2 in 5, respectively. These data indicated that 5 is a geometric isomer of illioliganone D with an E configuration isopentenyl unit, which was confirmed by the NOE correlations between δ_H 5.35 (H-11) and δ_H 4.60/4.64 (H₂-13). The baseline ECD curve and the optical rotatory data of [α]₂₀^D = 0 suggested that 5 is a racemate, which was confirmed by chiral analysis (Fig. S33 in Supporting information). Subsequently, the chiral HPLC separation of 5 afforded (+)-5 and (−)-5. The absolute configurations of (+)-5 and (−)-5 were assigned as 2S and 2R, respectively, by a comparison of their experimental spectra with those of 4.

Structurally diverse prenylated C₆—C₃ compounds have been reported to have inhibitory effects on RNA viruses. Therefore, compounds 1–3 and the isolated racemic mixtures 4 and 5 as well as their enantiomers [(+)-4, (−)-4, (+)-5, and (−)-5)] were tested for antiviral activity against CVB3, influenza A (H1N1), and influenza A (H3N2) [44]. As shown in Tables S1 and S2, compounds 1 and (+)-5 exhibited significant inhibitory activity against CVB3 with IC₅₀ values of 11.11 µmol/L and 1.11 µmol/L and SI values of 2.1 and 4.3, respectively, compared with the positive control ribavirin (IC₅₀ = 1173.56 µmol/L and SI = 7.0) but less effective than the capsid inhibitor pleconaril. On the other hand, despite their structural similarity, compounds 2 and (−)-5 were much less active, and their IC₅₀ values were > 33.33 µmol/L and > 11.11 µmol/L, respectively, indicating that stereo configurations of 17R in 1 and 2S in (+)-5 might be favorable for anti-CVB3 activity. Additionally, a pair of epimers 1 and 2 showed moderate inhibitory activity against influenza A (H1N1) with IC₅₀ values of 11.11 µmol/L and 11.11 µmol/L, respectively.

In conclusion, one pair of unusual spirocarbon epimers (spirooliganones C-D, 1 and 2), one dimeric prenylated C₆–C₃ compound (3), and two pairs of racemates [(+)-4/(−)-4 and (+)-5/(−)-5)] were isolated from the roots of I. oligandrum. Spirooliganones C-D represent a novel family of cyclic prenylated tetrahydropyrano-type C₆—C₃ derivatives possessing a unique 6/6/5/3 tetracyclic ring carbon skeleton. A possible biosynthetic pathway involving the Diels-Alder reaction of (−)-sabinene and cyclic prenylated tetrahydropyran-type C₆—C₃ compounds was proposed for compounds 1 and 2, which will inspire further biomimetic and total synthesis interests. The antiviral activity screening of all compounds showed that spirooliganone C and (+)-5 exhibited potent antiviral activities against CVB3. To a certain extent, the anti-CVB3 activities of a pair of spirocarbon epimers (1 and 2) and a pair of enantiomers [(+)-5 and (−)-5)] were related to their stereo configurations of C-17 and C-2, respectively.

Declaration of competing interest

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The authors report no declarations of interest.

Acknowledgments

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This work was supported by grants from the National Natural Science Foundation of China (Nos. 21732008 and 22177135). We are grateful to the Department of Instrumental Analysis of our institute for the acquisition of the IR and NMR spectra and the X-ray crystallographic measurements and analyses.

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Year 2022 volume 33 Issue 9

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doi: 10.1016/j.cclet.2022.02.050

Receive Date：2021-11-25
Online Date：2025-12-24
Published：2022-09-15

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Received：2021-11-25
Revised：2022-02-17
Accepted：2022-02-18

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^b Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China

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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

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Fig. 1 The structures of compounds 1–5.

Fig. 2 Key ¹H–¹H COSY and HMBC correlations for 1.

Fig. 3 Selected NOEs/ROESY correlations of compounds 1 and 2.

Fig. 4 Experimental ECD spectrum of 1 (red line) and the calculated spectra of 1 (red dashed line and blue dashed line).

Fig. 5 ORTEP drawing (left) and stacking diagram (right) of 1 and isopropanol.

Scheme 1 Plausible biogenetic pathway of 1 and 2.

Fig. 6 Experimental ECD spectra of (+)-4 and (−)-4 and the calculated spectra of (S)-4 and (R)-4.

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