Pepluanols C–D, Two Diterpenoids with Two Skeletons from

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Letter Cite This: Org. Lett. 2018, 20, 3074−3078

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Pepluanols C−D, Two Diterpenoids with Two Skeletons from Euphorbia peplus Luo-Sheng Wan,†,∥,⊥ Yin Nian,‡,⊥ Xing-Rong Peng,† Li-Dong Shao,† Xiao-Nian Li,† Jian Yang,‡ Ming Zhou,*,‡,§ and Ming-Hua Qiu*,† †

State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, P. R. China ‡ Key Laboratory of Animal Models and Human Diease Mechanisms, and Ion Channel Research and Drug Development Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, P. R. China § Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, United States ∥ Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, Pharmacy Department of Tongji Medical School, Huazhong University of Science and Technology, Wuhan 430030, P. R. China S Supporting Information *

ABSTRACT: Pepluanols C and D (1 and 2), featuring unprecedented 5/5/10 with out,out-[7.2.1]bicylcododecane core and 6/6/7/3 fused-ring skeletons, respectively, were isolated from Euphorbia peplus. Their chemical structures and absolute configurations were determined by a series of extensive spectroscopic methods, and X-ray diffraction analysis. In addition, pepluanols C and D showed 31.6 ± 8.3% and 30.5 ± 2.8% peak current inhibition on the Kv1.3 potassium channel at 30 μM.

D

iterpenoids, found in the genus Euphorbia (Euphorbiaceae) with their fascinating structures and broad biological properties, have attracted considerable attention from the areas of chemical synthesis,1 pharmacology2 and natural products.3 As one of the most well-known species in this genus, E. peplus has long been used in folkloric medicine to treat skin lesions, inflammatory diseases, asthma, diabetes, and cancers.4 Previous phytochemical studies revealed that the title plant is mainly composed of jatrophane, ingenane, and pepluane diterpenoids.5 As part of a program to explore structurally unique and bioactive components from natural resources, we investigated the whole plant of E. peplus and identified a number of novel diterpenoid derivatives with unprecedented 5/ 4/7/3, 5/6/7/3, and 5/5/8/3 fused-ring skeletons. In addition, all of these compounds possess the pseudobicyclic 1,5-diol subunits,6 and one of them (pepluanol A) has been recently achieved by elegant synthesis.7 As part of our continuous endeavor for bioactive diterpenoids from the remaining fraction of the same extract, we found another two interesting diterpenoids, pepluanols C and D (1 and 2, Figure 1), with unprecedented 5/5/10 and 6/6/7/3 fused-ring frameworks, respectively. It is particularly noteworthy that 1 contains a congested stereogenic triol moiety and two all-carbon quaternary stereocenters with a unique out,out-[7.2.1]bicylcododecane core, which are similar to those of ingenol mebutate © 2018 American Chemical Society

Figure 1. Structures of pepluanol C (1) and D (2).

and may pose a challenging target for the synthetic community.8 Further biological studies showed that compounds 1 and 2 moderately but selectively inhibited Kv1.3 peak current at 30 μM. Herein, the structural determinations, plausible biosynthetic pathways, and their Kv1.3 inhibitory effects were described. Pepluanol C (1) was obtained as colorless needles with the molecular formula C25H34O5, as determined by HRESIMS ([M + Na]+ m/z 437.2309, calcd 437.2304), requiring nine degrees of unsaturation. Its 1H NMR data (Table 1) displayed proton Received: April 9, 2018 Published: May 2, 2018 3074

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the 1H−1H COSY correlations of H2-7/H-8/H-9 and H-11/H12/H-13/H3-20, together with the HMBC correlations from exchangeable hydrogen (OH-4, δH 3.26) to C-4, C-5, and C-15; from H2-7 to C-14; from H-13 to C-14 and C-15; from H3-17 to C-5, C-6, C-7, and C-14; from H3-18 and H3-19 to C-9, C10, and C-11; and from H3-20 to C-12, C-13, and C-15. Moreover, the remainder of the five-member ring was defined by the HMBC correlations from H-1 to C-4, and C-15; from exchangeable hydrogen (OH-4) to C-3; and from H3-16 to C-1, C-2, and C-3. Finally, the angelate group was assigned to C-3 on the basis of the HMBC correlation from H-3 to C-1′. Thereby, the planar structure of 1 was established as depicted. Due to the overlap signals in 1, it was hard to judge the relative configuration by the ROESY correlations (except for the correlations between OH-4 and H-13, Figure 2 and Figure S9). Therefore, with the aid of the single crystal obtained from an n-Hexane/CH2Cl2 solution, the absolute configuration of 1 was directly determined by X-ray diffraction analysis with Cu Kα radiation [Flack parameter = −0.03(3)] (Figure 3).9

Table 1. 1H (600 MHz) and 13C (150 MHz) NMR Data for 1 and 2 in CDCl3(J in Hz) 1a δH 1 2 3 4 5 6 7 8 9 10 11

5.65 − 5.26 − 3.52 − 3.35 5.21 5.56 − 5.34

12 13 14 15 16 17 18 19 20

6.19 2.53 − − 1.74 1.07 1.07 1.19 1.35

brs s s brt; 1.74 m m d (10.9) d (16.6) m m

brs s s s d (4.3)

2a δC, type 135.0 (d) 136.7 (s) 82.3 (d) 83.4 (s) 80.0 (d) 55.5 (s) 26.4 (t) 125.8 (d) 142.0 (d) 37.7 (s) 139.7 (d) 127.7 (d) 37.1 (d) 214.9 (s) 72.4 (s) 15.4 (q) 19.2 (q) 31.3 (q) 24.1 (q) 15.0 (q)

δH 6.42 brs − − − 4.70 s − 5.17 brs 2.31 m 0.43 dd (11.5, 8.7) − 0.83 ddd (11.5, 8.7, 6.6) 2.00 m; 1.47 m 2.28 m − 2.92 m 1.86 d (1.0) 1.80 brs 1.14 s 1.14 s 1.20 d (7.6)

δC, type 149.7 (d) 132.2 (s) 201.5 (s) 74.3 (s) 68.7 (d) 130.0 (s) 125.8 (d) 38.9 (d) 26.3 (d) 19.7 (s) 23.2 (d) 29.8 38.3 82.2 48.3 15.7 18.8 29.5 15.1 15.4

(t) (d) (s) (d) (q) (q) (q) (q) (q)

a

For 1: 4-OH 3.26 (s), O-Angelate 6.19 (m), 2.03 (m), 1.95 (m), 168.3, 127.2, 139.7, 16.0, 20.7. For 2: 4-OH 3.66 (s), 5-OH 3.65 (s), 14-OH 1.67 (s).

signals attributed to an angelate group [δH 6.19 (1H, m, H-3′), 2.03 (3H, m, H-4′), 1.95 (3H, m, H-5′)], five olefinic methines [δH 5.65 (1H, brs, H-1), 5.21 (1H, m, H-8), 5.56 (1H, d, J = 10.9 Hz, H-9), 5.34 (1H, d, J = 16.6 Hz, H-11), and 6.19 (1H, m, H-12)], two oxymethines [δH 5.26 (1H, s, H-3), 3.52 (1H, s, H-5)], and five methyl groups [δH 1.74 (3H, brs, H3-16), 1.07 (3H, s, H3-17), 1.07 (3H, s, H3-18), 1.19 (3H, s, H3-19), and 1.35 (3H, d, J = 4.3 Hz, H3-20)]. In addition to carbon signals assigned to the angelate group (δC 168.3, 127.2, 139.7, 16.0, 20.7), the 13C NMR and DEPT spectra of 1 displayed resonances attributable to five methyls, one methylene, eight methines (five olefinic methine, and two oxygenated methines), and six quaternary carbons (one carbonyl, one olefinic carbon, and one oxygenated carbon), corresponding to the units in its 1 H NMR data. The above-mentioned spectroscopic data indicate that 1 was a tricyclic structure to account for the remaining three degrees of unsaturation. The planar structure of 1 was further constructed by 2D NMR spectroscopic analysis (Figure 2, Table S1). The structure of a [7.2.1]bicylcododecane core was established by

Pepluanol D (2) formed a colorless needle crystal and had a molecular formula of C20H28O4 as determined by HRESIMS at m/z 355.1885 [M + Na]+ (calcd 355.1885), with seven degrees of unsaturation. The 1D spectral data for 2 (Table 1) indicated the presence of a carbonyl group, two double bonds (both are trisubstituted), five methyls, one methylene, six methines (one oxygenated), and three quaternary carbons (two oxygenated). After deduction of the tree double-bond equivalents, a tetracyclic skeleton was still required to fulfill the degrees of unsaturation. In the 1H−1H COSY spectrum (Figure 4, Table S2), crosspeaks of H-7/H-8/H-9/H-11/H-12/H-13/H-15 (and H-20)/ H-1 revealed a connective structure. The HMBC correlations (Table S2) enabled assembly of this connective structure with the quaternary carbons and other functionalities. The HMBC correlations of OH-14/C-4, C-14, and C-15; H3-16/C-1, C-2,

Figure 2. Key 2D NMR correlations for pepluanol C (1).

Figure 4. Key 2D NMR correlations for pepluanol D (2).

Figure 3. X-ray structure of 1.

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biosynthetic pathways for 1 and 2 are postulated. As shown in Scheme 1, biosynthetically, both 1 and 2 might be originated from an ingenane-type precursor, specifically, 20-deoxyingenol 3-angelate, a typical and abundant component in E. peplus.5i For compound 1, a [1,3] alkyl shift of 20-deoxyingenol 3-angelate produces a less strained intermediate i with the out,out configuration.10 Then, this intermediate would undergo a ring opening reaction of the cyclopropanic ring to produce 1. For compound 2, hydrolysis and intramolecular retro-aldol reactions of 20-deoxyingenol 3-angelate would produce the intermediate ii, which would be further enolized to intermediate iii, followed by an aldol reaction to afford 2. Although there has been a total synthesis of ingenol from a similar 6/6/7/3 fused-ring intermediate in a direction opposite to that proposed in Scheme 1,11 biogenetically, ingenane-type diterpenoid is more likely to be derived from another tiglianetype precursor via a pinacol rearrangement.12 Kv1.3 is the predominant K+ channel in the activated effector memory T (TEM) cells and required for TEM cells proliferation and cytokine production.13 Therefore, Kv1.3 inhibitors can be used as TEM-cell-specific immunosuppressants for autoimmune disorders, such as multiple sclerosis, type-1 diabetes, asthma, and psoriasis without suppressing the native immune response.14 Previously, inspired by the traditional use of E. peplus for the treatment of asthma and psoriasis, we initially evaluated the Kv1.3 inhibitory effects of three novel diterpene analogues, pepluacetal, pepluanol A, and pepluanol B.6 Unexpectedly, these compounds exhibited different levels of inhibitions on Kv1.3. Therefore, in the present study, the inhibitory effects of pepluanol C (1) and pepluanol D (2) on Kv1.3 were continuously evaluated. As a result, compounds 1 and 2 showed moderate inhibitions on Kv1.3 peak currents at 30 μM (Figure 6). The inhibitory ratio is 31.6 ± 8.3% and 30.5

and C-3, along with the chemical shifts, indicated the presence of a six-membered ring A, consisting of C-1−C-4, C-14, and C15 in 2 with a methyl (CH3-16), a carbonyl, and two hydroxyl groups at C-2, C-3, C-4, and C-14, respectively. Furthermore, the HMBC correlations from OH-14 to C-8 and C-15, together with the above connective structure, established ring C as shown. Similarly, the HMBC correlations from OH-4 to C-5; from H-5 to C-3; from H-7 to C-5, C-6, C-14, and C-17; H3-17 to C-5, C-6, and C-7 led to assignment of the six-membered ring B, with a methyl (CH3-17) at C-6. Accordingly, the last gem-dimethylcyclopropane motif was verified by the HMBC correlations from H3-18 and H3-19 to C-9, C-10, and C-11. Thus, the planar structure of 2 was determined. As shown in Figure 4, the NOESY cross peaks from OH-14 to H-5, H-9, and H3-20 indicated that they were located on the same face of the structure; meanwhile, NOESY cross peaks between H-8 and H-15 revealed that the two hydrogen atoms were on the other face. However, the relative configurations of OH-4 could not be determined by the NOESY experiment due to the lack of direct correlations. After repeated attempts, a single crystal of 2 was obtained from a MeOH/CH2Cl2 solvent system. The X-ray diffraction data with Cu Kα radiation (Figure 5) strengthened the planar structure and relative configuration

Figure 5. X-ray structure of 2.

of 2 established by NMR data. Since H-9 and H-11 are αoriented in the gem-dimethylcyclopropane motif, characteristics of all biogenetically related precursors isolated from the genus Euphorbia (Scheme 1),3v,w the absolute configurations for 2 were allowed as 4R, 5R, 8S, 9R, 11R, 13R, 14R, 15S. Compounds 1 and 2 represent two unprecedented architectures featuring 5/5/10 with an out,out-[7.2.1]bicylcododecane core and 6/6/7/3 fused-ring skeletons. Plausible

Figure 6. Normalized current−voltage (I−V) curves of Kv1.3 current in the absence or presence of 30 μM 1 and 2. Currents were evoked from an HP of −80 mV by 200 ms depolarizations ranging from −40 mV to +60 mV in 10-mV increments at a 15-s interval. Data points reflect mean ± SEM of three to five determinations. The inhibition ratio for 1 and 2 are 31.6 ± 8.3% and 30.5 ± 2.8%, respectively.

Scheme 1. Plausible Biosynthetic Pathway of Pepluanol C− D (1−2)

± 2.8%, respectively. Meanwhile, compounds 1 and 2 have no effect on Cav1.2, 2.2, and 3.1, and hERG channels at the same concentration (Figures S1 and S2). Taken together, our bioactivity tests indicate that these two compounds may be developed into immunosuppressive lead structures without affecting other ion channel functions; however, sophisticated chemical modifications and in vitro and in vivo pharmaceutical studies are required. In summary, our findings of pepluanol C (1) and D (2) from E. peplus further demonstrate that the genus Euphorbia is not only the resource of novel diterpenoids with unprecedented skeletons, but also the natural pool for attractive Kv1.3 inhibitors. 3076

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01114. Experimental procedure, characterization data for compounds 1 and 2 (PDF) Accession Codes

CCDC 1441343 and 1441347 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (M.H.Q.). *E-mail: [email protected] (M.Z.). ORCID

Yin Nian: 0000-0002-9916-064X Li-Dong Shao: 0000-0003-4799-6784 Ming-Hua Qiu: 0000-0001-9658-1636 Author Contributions ⊥

L.-S.W. and Y.N. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was financially supported by the National Natural Science Foundation of China (Program No. 81403050, 81603000) and the NSFC-Joint Foundation of Yunnan Province (Program No. U1132604), the Natural Science Foundation of Yunnan province (Program No. 2016FB138), Yunnan Major Science and Technology Project (Program No. 2015ZJ002), and the Foundation of State Key Laboratory of Phytochemistry and Plant Resources in West China (Program No. P2015-KF03).

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