Isopenicins A–C: Two Types of Antitumor Meroterpenoids from the

Letter Cite This: Org. Lett. 2019, 21, 771−775

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Isopenicins A−C: Two Types of Antitumor Meroterpenoids from the Plant Endophytic Fungus Penicillium sp. sh18 Jian-Wei Tang,†,‡,⊥ Ling-Mei Kong,†,⊥ Wen-Yu Zu,§ Kun Hu,† Xiao-Nian Li,† Bing-Chao Yan,† Wei-Guang Wang,† Han-Dong Sun,† Yan Li,*,† and Pema-Tenzin Puno*,† †

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State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, and Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming 650201, Yunnan, People’s Republic of China ‡ University of Chinese Academy of Sciences, Beijing 100049, People’s Republic of China § Yunnan University of Traditional Chinese Medicine, Kunming 650500, Yunnan, People’s Republic of China S Supporting Information *

ABSTRACT: Isopenicins A−C (1−3), three novel meroterpenoids possessing two types of unprecedented terpenoidpolyketide hybrid skeletons, were isolated from the cultures of Penicillium sp. sh18. Their structures were determined through synergetic use of extensive spectroscopic analysis, quantum-chemical calculation with ANN−PRA analysis, and X-ray crystallographic analysis. Additionally, the inhibitory activities of these compounds on the Wnt/β-catenin signaling pathway were evaluated, and 1 was identified as a potent inhibitor of the Wnt signaling pathway.

F

KP404098), a strain isolated from the stems of I. eriocalyx var. laxif lora as well as the source of penicilfuranone A,4a an antifibrotic furancarboxylic acid reported in our previous study. In the molecular networking of Penicillium sp. sh18, a node (parent ion at m/z 487.436) was identified as andrastin A,6 a meroterpenoid as potential lead for anticancer drugs, by screening against GNPS spectral database (Figure 1a). It implied the existence of more meroterpenoids analogous to andrastin A in the metabolites of Penicillium sp. sh18. Therefore, in the hope of discovering novel antitumor meroterpenoids, we enlarged the fermentation with 36 kg of rice and finally afforded 600 g of crude extract. Subsequent indepth chemical investigation resulted in the discovery of isopenicins A−C (1−3) (Figure 1b), three novel meroterpenoids possessing two types of unprecedented terpenoid− polyketide hybrid skeletons. In addition, these novel meroterpenoids were initially evaluated for Wnt/β-catenin signaling pathway inhibitory activities. As a result, 1 was found to inhibit Wnt-dependent reporter activities and the expression of endogenous Wnt signaling target genes. Furthermore, 1

ungal secondary metabolites have always been considered as an important source for drug discovery by virtue of their diverse chemical structures and bioactivities.1 Among them, fungal meroterpenoids, a unique type of secondary metabolites derived from a hybrid terpenoid−polyketide pathway, have attracted great interest from the synthetic, biosynthetic, as well as pharmacological communities due to their complex and intriguing structures associated with a broad spectrum of biological properties.2 Over the past four decades, our group has focused on natural products from plants of the genus Isodon,3 one of the most important medicinal plant taxa widely distributed in southwest China. As part of an ongoing research effort toward discovering structurally novel antitumor agents, studies on endophytic fungi from Isodon species have also been initiated by us in recent years.4 Up to now, more than 1000 strains have been isolated and conserved in our laboratory. Recently, a systematic screening of the secondary metabolites of these strains has been conducted by using HPLC/UV profile analysis, and some of them were further subjected to the LC−MS/MS−GNPS (Global Natural Product Social Molecular Networking) database analysis.5 The GNPS analysis highlighted Penicillium sp. sh18 (GenBank Accession No. © 2019 American Chemical Society

Received: December 17, 2018 Published: January 14, 2019 771

DOI: 10.1021/acs.orglett.8b04020 Org. Lett. 2019, 21, 771−775

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Organic Letters

Figure 1. (a) Molecular networking of Penicillium sp. sh18. (b) Structures of isopenicins A−C (1−3).

C-15′ linkage. Hereto, the planar structure of 1 have been elucidated (Figure 2). To explore the relative configurations of 1, we tentatively assigned aldehydic carbon C-21 as α-oriented. In the ROESY spectrum of 1, the correlations of H-21/H3-20 and H-21/H319 suggested H3-20 and H3-19 should be α-oriented like H-21. In addition, the correlation of H-9/H-5 and lack of the correlation between H-5 and H-21 assigned the β-orientation of H-9 and H-5. Moreover, the key ROESY correlations of H15′/H-9 and H-15′/H-11 assigned the configuration of C-16 as R*, and the whole ring D was β-oriented. The configuration of C-3 was tentatively determined as the α-orientation by comparing the chemical shift, multiplicity, and coupling constants of H-3 with those of andrastin A (δH 4.62, dd, J = 2.4, 2.4 Hz), considering that the ROESY correlations of H-3/ H3-19, H-3/H-2α, and H-3/H-2β were not persuasive evidence due to their relative vicinal position (Figure 2). For the configuration of C-5′, we assumed that 1 might be generated by a Michael addition of plausible biogenetic precursors (Scheme S1), andrastin A, and gregatin A7 ([α]20D = −165.6, c = 0.30, CHCl3) or its enantiomer aspertetronin A7 ([α]20D = +163.8, c = 0.45, CHCl3). As the precursor gregatin A ([α]23D = −155.7, c = 0.20, CHCl3) had been successfully obtained in this study, the R-configuration of C-5′ was established. However, the configuration of C-15′ was unable to be determined under the current available data. In order to unambiguously determine the structure and the stereochemistry of 1, we tried our best to obtain a single crystal for X-ray analysis. After many attempts, a very thin but suitable crystal was obtained by using vapor exchange of methanol and water in a closed tube. Subsequently, a single-crystal X-ray diffraction experiment, using the anomalous scattering of Cu Kα radiation, provided the conclusive evidence for the structure and the absolute configuration of 1 with the Flack parameter of 0.04(4) (CCDC no. 1885462), which revealed the absolute configuration as 3S,5R,8S,9R,10S,13R,14R,16R,5′R,15′R (Figure 3). Isopenicin B (2) possessed the same molecular formula C44H58O11 as 1 on the basis of HRESIMS (m/z 785.3858 [M + Na]+, calcd for 785.3871), also indicating 16 indices of hydrogen deficiency. The 13C NMR and DEPT spectra (Table S1) of 2 were almost identical to that of 1, except for the subtle differences in chemical shifts of C-9, C-15, C-16, C-17, C-25, and C-15′ with Δ +0.8, −1.3, +0.8, +1.2, −0.5, and +0.5 ppm shifted, respectively. The 1H NMR spectrum (Table S1) of 2 was also very similar to that of 1, with the most notable differences being that the H-9 (δH 2.11, overlapped), H-14′a

selectively inhibited the growth of CRC cells with constitutive Wnt signaling and caused obvious G2/M cell cycle arrest and subsequent apoptosis. Herein, we report the isolation, structure elucidation, and biological study of the novel meroterpenoids from endophytic fungus Penicillium sp. sh18. Isopenicin A (1) was initially obtained as a white amorphous powder. Its molecular formula was determined to be C44H58O11 from the HRESIMS ion peak at m/z 785.3893 ([M + Na]+, calcd for 785.3871), which corresponds to 16 indices of hydrogen deficiency. Interpretation of the 13C NMR and DEPT spectra (Table 1) revealed 44 carbon signals attributable to 12 methyls (including two methoxyl), six methylenes, 10 methines (one oxygenated, five olefinic, and one aldehydic), and 16 quaternary carbons. The diagnostic aldehydic carbon signal at δC 204.1 (C-21) corresponding to the aldehydic proton at δH 10.11 (s), together with two lowfieled carbonyl carbon signals at δC 215.1 (C-15) and δC 210.5 (C-17) indicated that 1 might be an analogue of andrastin A. The remaining proton resonances were assigned as in Table 1 by comprehensively analyzing the 1H NMR and HSQC spectra. Analysis of the HMBC spectrum (Table 1) gave rise to the conclusion that the architecture of 1 was formed by two subunits, parts A and B (Figure 2). The structure of part A was almost identical to andrastin A, which could be ascertained by the following evidence: H2-1/H2-2/H-3 and H2-6/H2-7 spin systems confirmed by the 1H−1H COSY spectrum and the HMBC correlations from H2-1 to C-5 (δc 47.9), from H2-2 to C-1 (δc 28.2) and C-3 (δc 76.9), and from H-3 to C-4 (δc 37.2), C-5, and C-3-OAc (δc 170.2), from H-11 to C-9 (δc 54.1), C-10 (δc 52.4), and C-13 (δc 60.9), from H3-22 to C-11 (δc 126.0), C-12 (δc 133.9) and C-13, from H3-23 to C-12, C13, C-14 (δc 72.0), and C-17, and from H3-25 to C-15, C-16 (δc 58.0), and C-17. The structure of part B was established by the spin systems H3-16′/H2-15′/H-14′, H3-11′/H2-10′/H-9′/ H-8′, and H-7′/H-6′ as confirmed by 1H−1H COSY spectrum and the HMBC correlations from H3-16′ to C-15′ (δc 37.9) and C-14′ (δc 31.8), from H2-14′ to C-2′ (δc 196.4) and C-3′ (δc 108.2), from H3-13′ to C-4′ (δc 197.7), C-5′ (δc 90.8), and C-6′ (δc 125.1), and from H-7′ to C-8′ (δc 127.4), C-9′ (δc 139.7), and C-5′. Moreover, the chemical shifts of C-15 and C17 evidently shifted to the low-field and the chemical shift of C-16 shifted to the high-field in part A by comparing those of andrastin A in combination with the key HMBC correlations from H3-16′ to C-16 and from H3-25 to C-15′ confirmed the conclusion that the connection of parts A and B via C-16 and 772

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Organic Letters Table 1. 1H NMR (600M Hz), 13C NMR (150M Hz), and HMBC Data of 1 [δ (ppm), J (Hz)] Recorded in Chloroform-d 1 δH, mult (J)

δC, type

α 2.32 (dt, 13.0, 3.5), β 1.04 (dt, 13.0, 4.0) a 1.62 (m), b 1.50 (m) 4.69 (dd, 2.8, 2.8)

28.2 CH2

2, 3, 5, 10, 21

23.4 CH2 76.9 CH

3, 4, 10 1, 2, 4, 5, 18, 19, 3-OAc

no. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 24OMe 25 2′ 3′ 4′ 5′ 6′ 7′ 8′ 9′ 10′ 11′ 12′ 12′OMe 13′ 14′ 15′ 16′ 3-OAc

1.75 (overlapped) α 1.99 (m), β 1.76 (overlapped) α 2.47 (dt, 13.3, 4.1), β 2.83 (td, 13.3, 3.4) 2.11 (overlapped)

5.77 (s)

0.92 (s) 0.87 (s) 1.19 (s) 10.11 (s) 1.71 (s) 1.26 (s) 3.62 (s) 1.23 (s)

5.41 6.04 5.94 5.73 2.10 0.99

(d, 15.3) (dd, 15.3, 10.4) (dd, 14.9, 10.4) (dt, 14.9, 6.5) (overlapped) (t, 7.6)

3.81 (s) 1.38 (s) a 3.68 (dt, 14.1, 12.3), b 2.96 (dt, 14.1, 3.0) 2.63 (m) 0.79 (d, 6.7) 1.96 (s)

37.2 47.9 16.8 30.8

C CH CH2 CH2

39.6 C 54.1 CH 52.4 126.0 133.9 60.9 72.0 215.1 58.0 210.5 26.4 21.4 19.4 204.1 19.2 17.3 167.7 51.9

C CH C C C C C C CH3 CH3 CH3 CH CH3 CH3 C CH3

15.6 196.4 108.2 197.7 90.8 125.1 131.1 127.4 139.7 25.6 13.2 163.2 51.7

CH3 C C C C CH CH CH CH CH2 CH3 C CH3

22.4 CH3 31.8 CH2 37.9 13.6 170.2 21.3

CH CH3 C CH3

HMBC

4, 6, 9, 10, 21 8 5, 6, 8, 9, 14, 20

Figure 2. 1H−1H COSY (bold), selected HMBC (green arrows), and key ROESY (black arrows) correlations of 1.

1, 8, 10, 11, 12, 14, 20, 21 8, 9, 10, 13, 22

3, 4, 5, 19 3, 4, 5, 18 7, 8, 9, 14 1, 10 11, 12, 13 12, 13, 14, 17

Figure 3. X-ray crystallographic structure of 1.

detailed analysis of the 1H−1H COSY and HMBC spectra (Table S1 and Figure S2). By carefully analyzing the ROESY spectrum of 2, we found the pattern of all the key correlations H-21/H3-20, H-21/H3-19, H-9/H-5, H-15′/H-9, and H-15′/ H-11 could be observed, and the chemical shift, multiplicity, and coupling constants of H-3 in 2 were almost identical to those of 1 (Figure S2). This evidence implied that the relative configurations of part A in 2 were the same as those in 1. Therefore, the only difference in configuration should be C15′, which established the absolute configuration as 3S,5R,8S,9R,10S,13R,14R,16R,5′R,15′S. In order to validate the correctness of 2, ANN-PRA8 (artificial neural networks pattern recognition analysis) was selected to be the validation method in absence of the ideal crystal. The calculation followed the instructions of ANN-PRA, which required the optimization of the geometry at the B3LYP/6-31G* level in the gas phase and calculation of the NMR shielding tensors at the mPW1PW91/6-31G* level in the gas phase and the mPW1PW91/6-31G** level with the PCM model in chloroform. The results contained 72 output parameters, which were calculated in two reference standards (TMS and MSTD), gave rise to the conclusion that the structure of 2 was correct (Figures 4 and S5). In addition, the absolute configuration of 2 was validated by TDDFT (time-dependent density functional theory) calculations9 of its ECD spectrum (Figures 4 and S7). Isopenicin C (3) had the molecular formula C38H48O11 with 15 indices of hydrogen deficiency, which was determined by the HRESIMS (m/z 703.3113 [M + Na]+, calcd for 703.3089). Comprehensive analysis of the NMR data (Table S2) of 3 suggested that the gross structure of 3 also comprised two partial structures. In addition, the subunit, part A, could be easily confirmed as same as that in 1 and 2, according to the discernible signals C-15 (δc 215.0), C-17 (δc 211.8), and C-21 (δc 204.6) in 13C NMR data and the key correlations in the

24 15, 16, 17, 15′

5′, 5′, 6′, 7′, 8′, 9′,

7′, 8′ 8′, 9′ 10′ 10′ 9′, 11′ 10′

12′ 4′, 5′, 6′ 2′, 3′, 15′, 16′ 25, 14′, 16′ 16, 14′, 15′

(δH 3.68, dd, J = 14.1, 12.3 Hz), H-14′b (δH 2.96, dd, J = 14.1, 3.0 Hz), and H-1β (δH 1.04, dt, J = 13.0, 4.0 Hz) in 1 shifted to high field at δH 1.90 (br s), δH 3.52 (dd, J = 14.0, 11.6 Hz), δH 2.53 (dd, J = 14.0, 2.5 Hz), and δH 0.73 (dt, J = 13.0, 4.3 Hz) in 2, respectively. Therefore, we assumed that 2 might share the same planar structure with 1 but differed subtly in relative configurations. This assumption could also be confirmed by 773

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pathway inhibitory activities, which were conducted in HEK293 cells stably transfected with Wnt3a, Renilla, and SuperTopflash luciferase (ST-Luc).11 As shown in Figure 5a, incubation with 1 resulted in a dose-dependent decrease in Wnt3a induced ST-Luc transcription with an IC50 value of 9.80 ± 1.87 μM. The Wnt signaling pathway is aberrantly activated in colon cancers.12 Thus, the Wnt signaling inhibitory activity of 1 was further investigated in Wnt-dependent colorectal cancer cells (CRC). SW620 and HCT116 cells were transiently transfected with the Wnt/β-catenin signaling reporter ST-Luc and Renilla. The elevated ST-Luc activity was significantly decreased by 1 in both SW620 and HCT116 cells. We further studied the effect of 1 on the expression of endogenous Wnt target genes using Western blot analysis and found that the expression of Axin 2, c-myc, and survivin was obviously suppressed in SW620 and HCT116 cells exposed to 1 (Figure 5b). β-Catenin is the pivotal component in the canonical Wnt signaling pathway that is phosphorylated by the destruction complex and then ubiquitinated and degraded through the proteasome pathway.13 One hallmark of activation of Wnt signaling is the stabilization and accumulation of nonphosphoβ-catenin (active β-catenin) in colorectal cancer cells. To investigate the molecular mechanism of 1 that inhibits Wnt signaling pathway, the protein levels of total β-catenin and active β-catenin in 1-treated colon cancer cell lines were checked. As shown in Figure 5b, obvious reduction active form of β-catenin in cells treated with 1 was detected. Wnt signaling plays a critical role in regulation of CRC cell growth, proliferation, and survival.12b Therefore, the cytotoxic effects of 1 were investigated by MTS assay. As shown in Figure 5c and Figure S9, consistent with the Wnt inhibitory activity of the tested compounds, only 1 and 2 exhibited proliferation inhibitory effect in the MTS assay. Moreover, 1 exhibited stronger growth inhibitory effects on colon cancer cells (SW480, SW620, HCT116, and CaCo2) than other types of cancers (SMMC-7721, A549, and MCF-7) suggesting 1 selectively suppresses the Wnt pathway.

Figure 4. ANN-PRA results and calculated and experimental ECD spectra of 2 and 3.

HMBC and ROESY spectra (Table S2). The remaining signals in 13C NMR data could be assigned as one singlet methyl at δC 32.8 (C-9′), one methoxyl at δC 56.0 (MeO-4′), one methylene at δC 40.3(C-1′), one olefinic methine at δC 107.5 (C-3′), and six quaternary carbons at δC 125.7 (C-2′), 147.8 (C-4′), 131.7 (C-5′), 145.2 (C-6′), and 121.5 (C-7′). These signals implied that the part B in 2 was 2,3-dihydroxy-1methylcarbonyl-4-methoxyl-6- ubstituted benzene, which could be further established by the HMBC correlations from H2-1′ to C-2′, C-7′, C-3′, and C-16 (δc 55.9), from H-3′ to C2′, C-4′, and C-5′, from H3-9′ to C-8′ and C-7′, and from the H3-4′-OMe to C-4′ (Table S2 and Figure S3). The key ROESY correlation H2-1′/H-9 suggested the configuration of C-16 could also be assigned as R like 1 and 2 (Figure S3). Thus, the absolute configuration of 3 could be determined as 3S,5R,8S,9R,10S,13R,14R,16R. The structure and the absolute configuration of 3 were also validated by the ANN-PRA analysis with and the TDDFT calculations of ECD spectrum (Figures 4, S6, and S8). Aberrant activation of the Wnt/β-catenin signaling pathway is involved in the development and progression of various cancers. Antagonists of Wnt/β-catenin signaling might be very potent to for development into effective antitumor agents.10 Compounds 1, 2, 3, and andrastin A were evaluated the Wnt

Figure 5. (a) Wnt pathway inhibitory activities of 1, 2, 3, and andrastin A in HEK293W cells. (b) Compound 1 inhibited luciferase activity in a concentration-dependent manner in CRC. (c) Compound 1 suppressed the expression of Wnt target genes, Axin 2, c-myc, and survivin, as well as the expression of total and active β-catenin in SW620 and HCT116 cells. (d) Effects of 1 and analogues on the growth of various cell lines (48 h). (e) Representative histograms depicting cell-cycle distribution as analyzed by flow cytometry in SW620 and HCT116 cells treated with indicated concentrations of 1 for 24 h. Counts of G2/M phase cells increased remarkably in the treated cells in a concentration-dependent manner. (f) SW620 and HCT116 cells were incubated with 1 at concentrations of 5, 10, and 20 μM for 48 h. Apoptosis was analyzed by Annexin V-FITC/PI staining. 1 induced dramatic apoptosis in SW620 and HCT116 cells. 774

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Kong, L. M.; Li, X. N.; Du, X.; Luo, S. H.; Liu, Y.; Li, Y.; Sun, H. D.; Pu, J. X. Org. Lett. 2016, 18, 1108−1111. (c) Tang, J. W.; Wang, W. G.; Li, A.; Yan, B. C.; Chen, R.; Li, X. N.; Du, X.; Sun, H. D.; Pu, J. X. Tetrahedron 2017, 73, 3577−3584. (5) Wang, M. X.; et al. Nat. Biotechnol. 2016, 34, 828−837. See the Supporting Information for full the reference. (6) Uchida, R.; Shiomi, K.; Inokoshi, J.; Sunazuka, T.; Tanaka, H.; Iwai, Y.; Takayanagi, H.; Omura, S. J. Antibiot. 1996, 49, 418−424. (7) Burghart-Stoll, H.; Bruckner, R. Eur. J. Org. Chem. 2012, 2012, 3978−4017. (8) Zanardi, M. M.; Sarotti, A. M. J. Org. Chem. 2015, 80, 9371− 9378. (9) Pescitelli, G.; Bruhn, T. Chirality 2016, 28, 466−474. (10) Kahn, M. Nat. Rev. Drug Discovery 2014, 13, 513−532. (11) Li, X. Y.; Wang, Y. Y.; Yuan, C. M.; Hao, X. J.; Li, Y. Nat. Prod. Bioprospect. 2013, 3, 24−28. (12) (a) Oving, I. M.; Clevers, H. C. Eur. J. Clin. Invest. 2002, 32, 448−457. (b) Klaus, A.; Birchmeier, W. Nat. Rev. Cancer 2008, 8, 387−398. (13) MacDonald, B. T.; Tamai, K.; He, X. Dev. Cell 2009, 17, 9−26.

The propidium iodide (PI) and Annexin V-FITC/PI double staining were applied further to examine cell cycle distribution and cell apoptosis induced by 1. As shown in Figure 5d, 1 caused G2/M cell cycle arrest in SW620 and HCT116 cells, with the percentage running up to 55.80% and 40.77%, respectively. In the apoptosis assay (Figure 5e), the Annexin V positive population, representing cells undergoing apoptosis, drastically increased in a dose-dependent manner in SW620 and HCT116 cells treated with 1. The proportions of apoptotic cells in SW620 and HCT116 cells were 7.50% and 9.42%, respectively, while they dramatically increased to 80.70% and 81.50% after treatment of 1 for 48 h. The above data suggest that 1 is a novel Wnt signaling antagonist and selectively inhibits the growth of CRC by suppressing the Wnt signaling pathway.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b04020. Detailed experimental procedure; X-ray crystal data for compound 1; ANN-PRA results and calculated ECD spectra for compounds 2 and 3; 1D and 2D NMR, MS, IR, UV, and ECD spectra for compounds 1−3 (PDF) Accession Codes

CCDC 1885462 contains 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]. *E-mail: [email protected]. ORCID

Wei-Guang Wang: 0000-0003-3395-767X Pema-Tenzin Puno: 0000-0001-5212-3000 Author Contributions ⊥

J.-W.T. and L.-M.K. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This project was supported financially by the National Natural Science Foundation of China (Nos. 81874298, 81673329, 81773783, and 81603161).

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REFERENCES

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DOI: 10.1021/acs.orglett.8b04020 Org. Lett. 2019, 21, 771−775