Saroclides A and B, Cyclic Depsipeptides from the Mangrove-Derived

Mar 2, 2018 - Two new depsipeptides (1 and 2), together with three known related compounds, pestalotin (3), pestalotiopyrone L (4), and PC-2 (5), were...
0 downloads 0 Views 2MB Size
Download PDF
Note Cite This: J. Nat. Prod. XXXX, XXX, XXX−XXX

pubs.acs.org/jnp

Saroclides A and B, Cyclic Depsipeptides from the Mangrove-Derived Fungus Sarocladium kiliense HDN11-112 Wenqiang Guo,†,⊥ Shuai Wang,‡,⊥ Na Li,† Feng Li,† Tianjiao Zhu,† Qianqun Gu,† Peng Guo,*,‡ and Dehai Li*,†,§ †

Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, People’s Republic of China ‡ Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, People’s Republic of China § Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, People’s Republic of China S Supporting Information *

ABSTRACT: Two new depsipeptides (1 and 2), together with three known related compounds, pestalotin (3), pestalotiopyrone L (4), and PC-2 (5), were discovered in the extract of a mangrove derived fungus Sarocladium kiliense HDN11-112. The structures of saroclides A and B were established by interpretation of extensive NMR spectroscopic data and X-ray crystallographic analysis. Compound 1 was also produced by Simplicillium lamellicola HDN13-430. Compounds 1 and 2 were inactive against five cancer cell lines and four pathogenic microorganisms, while compound 1 showed a lipid-lowering effect. lowering properties and a patent application filed in China.14 Herein, we report the details of the isolation, structure elucidation, and biological activities of compounds 1 and 2.

C

yclic depsipeptides, structurally recognized as cyclic peptides with ring closure at an ester linkage,1 represent a unique family of secondary metabolites with impressive pharmacological effects including nematocidal,2 immunosuppressive,3 antitumor,4 antitubercular,5 and SHIP1 (Src homology 2 domain-containing inositol phosphatase) inhibitory activities.6 Biogenetically, their macrocyclic backbones are formed from both polyketide synthases (PKS) and nonribosomal peptide synthetases (NRPS) by using acetate units and amino acids as primary building blocks.2,7 In addition to the variation in the size of the macrocyclic ring, number, and type of amino acids, further modification, including oxidation, reduction, methylation, halogenation, and epimerization of the PKS-NRPS backbones, further extends their structural diversity.8 While exploring bioactive secondary metabolites from marine-derived microorganisms,9 a fungus Sarocladium kiliense strain HDN11-112, isolated from the rhizosphere soil of the mangrove plant Aricennia marina, was selected because extracts had an interesting HPLC profile. Further fractionation of the crude extract led to the discovery of two new cyclic depsipeptides that were named saroclides A and B (1 and 2), together with the biogenetically related known polyketides pestalotin (3),10 pestalotiopyrone L (4),11 and PC-2 (5).12 Saroclides A and B are a pair of epimers differing in the configuration of the proline units, L- and D-Pro respectively, which is rare among the NRPS metabolites from fungi with only a few cases reported.13 In addition, compound 1 was also discovered as the main product from an Antarctica derived fungus Simplicillium lamellicola HDN13-430; this showed lipid© XXXX American Chemical Society and American Society of Pharmacognosy

The fungal strain S. kiliense HDN11-112 was cultured, extracted, and subjected to repeated silica gel, sephadex LH-20 column chromatography, and preparative HPLC, yielding the new compounds 1 (15.0 mg) and 2 (5.0 mg). Saroclide A (1) was obtained as a white powder. The molecular formula was determined as C25H32N2O5 on the basis of HRESIMS analysis, indicating 11 degrees of unsaturation. Analysis of the 1D NMR data (Table 1) of 1 revealed the presence of two sp3 methyls, eight sp3 methylenes, three sp3 methines with one oxygenated (δC 74.0/δH 4.91, CH-7), and 12 sp2 hybridized carbons including a monosubstituted benzene Received: August 10, 2017

A

DOI: 10.1021/acs.jnatprod.7b00644 J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products

Note

Table 1. 1H (500 MHz) and 13C (125 MHz) NMR Spectroscopic Data of Saroclides A (1) and B (2) in CDCl3 1 position

δC, type

1 2

167.1, C 48.1, CH2

3 4 5 6

193.7, C 138.8, C 138.0, CH 31.2, CH2

7 8 9 10 11 12 13 14 15 16

74.0, CH 33.7, CH2 18.9, CH2 13.8, CH3 11.6, CH3 170.1, C 59.4, CH 29.2, CH2 24.3, CH2 47.4, CH2

17 18

170.7, C 51.5, CH

19

38.0, CH2

20 21 22 23 24 25 NH-18

135.6, 129.1, 128.7, 127.2, 128.7, 129.1, −

C CH CH CH CH CH

δH (J in Hz) − 3.67, d (15.0); 3.45, d (15.0) − − 6.61, t (5.1) 2.54, d (19.0); 2.46, d (19.0) 4.91, m 1.85, 1.47, m 1.26, m 0.92, t (7.4) 1.75, s − 4.39, t (4.2) 1.98, m 1.77, m; 1.66, m 3.85, m; 2.89, q (8.0) − 5.16, ddd (11.0, 9.8, 5.8) 3.07, dd (12.7, 10.5); 2.95, dd (13.0, 5.8) − 7.29, m 7.26, m 7.23, m 7.26, m 7.29, m 6.98, d (9.8)

H2-8/H2-9/H3-10 and the HMBC correlations from H2-2 to C1/C-3/C-4 and from H3-11 to C-3/C-4/C-5 deduced the presence of the 7-hydroxy-4-methyl-3-oxodec-4-enoic acid (HMODA) unit. Finally, the gross structure of 1 was established by connection of the two amino residues and the oxodecanoic acid unit based on the HMBC correlations from H-7 to C-12 and from NH-18 to C-1/C-18, as well as the consideration of the molecular formula. The geometry of Δ4,5 was deduced as E by the NOESY correlation between H2-6 and H3-11. The presence of Dphenylalanine and L-proline in 1 was determined by acid hydrolysis followed by HPLC analysis of the derivatized Marfey reagent products.15 As the HMODA unit was unstable during methanolysis using MeONa/MeOH, the absolute configuration of C-7 could not be determined by Mosher’s method. Crystals of 1 were obtained, and the 7R, 13S, 18R absolute configurations and the trans conformations of the amide bonds between proline and phenylalanine were unambiguously determined based on X-ray diffraction analysis (Flack parameter = −0.1) using Cu Kα radiation (Figure 2).

2 δC, type 166.9, C 48.2, CH2 193.9, C 138.7, C 138.3, CH 31.3, CH2 74.0, CH 33.8, CH2 18.9, CH2 13.9, CH3 11.7, CH3 170.1, C 59.2, CH 29.2, CH2 24.4, CH2 47.0, CH2 170.6, C 51.6, CH 38.1, CH2 136.0, 129.1, 128.6, 127.1, 128.6, 129.1, −

C CH CH CH CH CH

δH (J in Hz) − 3.63, d (14.8); 3.44, d (14.8) − − 6.61, t (5.1) 2.56, d (18.8); 2.44, d (18.8) 4.87, m 1.89, 1.51, m 1.29, m 0.93, t (7.4) 1.75, s − 4.38, t (4.2) 1.95, m 1.73, m; 1.62, m 3.75, m; 2.84, q (7.8) − 5.09, ddd (12.6, 9.8, 5.8) 3.10, dd (13.0, 10.2); 2.93, dd (13.0, 5.8) − 7.26, m 7.24, m 7.22, m 7.24, m 7.26, m 6.52, d (9.8)

Figure 2. ORTEP drawing of crystal structure of 1.

and four carbonyls (δC 193.7, 170.7, 170.1, and 167.1). The planar structure was determined by the analysis of the 2D NMR data (Figure 1). The COSY correlations (NH-18/H-18/H2-19,

Saroclide B (2) was isolated as a white powder with the same molecular formula as that of 1. The NMR spectroscopic data for 2 (Table 1) were almost identical to those of 1, except for the proton signals of the proline unit. The 2D NMR data (Figure 1) of compounds 1 and 2 showed they shared the same planar structure. Compound 2 had a D-Pro, instead of L-Pro residue, as demonstrated by the Marfey method analysis, which was in agreement with the differences of chemical shifts. The E configuration of Δ4,5 was also deduced by the NOESY correlation between H2-6 and H3-11 (Figure 3). The NOESY correlation between H-7 and H-13 suggested that they oriented to the same face of the macrocyclic ring, and the absolute configuration of C-7 was deduced to be R, the same as 1. The known polyketides pestalotin (3),10 pestalotiopyrone L (4),11 and PC-2 (5),12 which were biogenetically related to the HMODA unit, were identified based on comparison of their sepctroscopic data with literatures data. The new compounds 1 and 2 were inactive against HeLa, BEL-7402, HEK-293, HCT-116, and A549 cell lines, Escherichia coli, Staphylococcus aureus, Candida albicans, and Bacillus subtilis. Compound 1 significantly decreased oleic acid (OA)-elicited lipid accumulation as determined from oil-red O staining results (Figure 4B) as well as intracellular cholesterol (Figure 4C) and triglyceride (Figure 4D). Simultaneously, compound 1 did not show obvious cytotoxicity on the tested HepG2 cells at

Figure 1. Key COSY and HMBC correlations of 1 and 2.

H-21/H-22/H-23/H-24/H-25) and the HMBC correlations from H-18 to C-17 and from H2-19 to C-20/C-21/C-25 suggested the existence of a phenylalanine residue (Figure 1). The proline unit was deduced by COSY correlations (H-13/ H2-14/H2-15/H2-16), and the HMBC correlations from H-13/ H2-14 to the ester carbonyl C-12. The two amino acids were linked supported by the HMBC correlation from H-16 (δH 3.85) to C-17. Further COSY correlations of H-5/H2-6/H-7/ B

DOI: 10.1021/acs.jnatprod.7b00644 J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products

Note

work, the two enantiomer saroclides A (1) and B (2) were generated simultaneously from a single strain, S. kiliense HDN11-112, which indicates a relaxed stereoselectivity of the enzyme catalyzed in the PKS-NRPS biosynthetic pathway. In contrast, only compound 1 was produced by the main extract of S. lamellicola HDN13-430.14

■

EXPERIMENTAL SECTION

General Experimental Procedures. Optical rotations were measured with a JASCO P-1020 digital polarimeter. UV spectra were recorded on Waters 2487. IR spectra were recorded on a NICOLET NEXUS 470 spectrophotometer on KBr discs. 1H NMR, 13 C NMR, DEPT, and 2D NMR spectra were recorded on an Agilent 500 MHz DD2 spectrometer using TMS as an internal standard. HRESIMS and ESIMS data were obtained using a Thermo Scientific LTQ Orbitrap XL mass spectrometer. X-ray crystal data were measured on an Xcalibur Eos Gemini single-crystal diffractometer (Cu Kα radiation). Column chromatography (CC) were performed on silica gel (100−400 mesh, Qingdao Marine Chemical Factory), Sephadex LH-20 (Amersham Biosciences), and ODS resin (50 mm, Merck). Analyzed HPLC used a C18 column [YMC-Pack ODS-A, 4.6 mm × 250 mm, S-5 μm, 1 mL/min]. Preparative HPLC collection used a C18 column [YMC-Pack ODS-A, 10 mm × 250 mm, S-5 μm, 3 mL/min]. Fungal Material. The fungal strain S. kiliense HDN11-112 was isolated from the rhizosphere soil of the mangrove plant A. marina and identified by the sequence of the ITS region (GenBank accession number MF538737) with 100% similarity to S. kiliense. The fungal strain S. lamellicola HDN13-430 was isolated from marine sediment

Figure 3. Key NOESY correlations of 2.

20 μM, which indicated that the lipid lowering activity was not due to cytotoxicity (Figure 4A). In the majority of cases, only one of the two enantiomeric structures is biosynthesized by an organism because of stereoselectivity of the enzyme catalyzed.16 Those enantiomerically opposite metabolites are usually produced with one enantiomer from one species and the other from a different species, or a different genera.17 However, as presented in this

Figure 4. Effects of compound 1 on OA (oil acid)-elicited intracellular lipid accumulation. (A) Cell viability. (B) Lipid accumulation determined by oil-red O staining at 358 nm. (C) Intracellular levels of total cholesterol and (D) triglycerides. Cells were treated with compound 1 or simvastatin (10 μM, as positive control) in DMEM + 100 μM OA or with DMEM alone (as blank) or DMEM + 100 μM OA (as negative control) for 24 h. Cell viability was tested by MTT assay, and neutral lipids were determined by spectrophotometry at 358 nm after oil-red O staining. Intracellular levels of total cholesterol and triglycerides were measured by kits according to the manufacturer’s instructions. Bars depict the means ± SEM of at least three experiments. ##p < 0.01, OA versus Blank; *p < 0.05, **p < 0.01, test group versus OA group. OA: oleic acid. C

DOI: 10.1021/acs.jnatprod.7b00644 J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products

Note

collected in Antarctic Pritz Bay, and the ITS region (GenBank accession number KY794926) showed 100% similarity to S. lamellicola. The strains were deposited at the Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, People’s Republic of China. Fermentation. Erlenmeyer flasks (1 L) containing 300 mL of fermentation media were directly inoculated with spores (S. kiliense HDN11-112). The flasks were cultured under the static conditions at 20 °C for 45 days. The fungus S. lamellicola HDN13-430 was cultured in Erlenmeyer flasks (500 mL) containing 100 mL of fermentation media incubated at 28 °C, with agitation at 180 rpm for 9 days. The media contained maltose (2%), mannitol (2%), glucose (1%), sodium glutamate (1%), yeast extract (0.3%), corn syrup (0.1%), KH2PO4 (0.05%), and MgSO4·7H2O (0.03%) dissolved in naturally collected seawater (Huiquan Bay, Yellow Sea, Qiangdao, China). Extraction and Purification. The S. kiliense HDN11-112 fermentation broth (30 L) was filtered through cheese cloth to separate the supernatant from the mycelia. The supernatant was extracted with EtOAc. The mycelia was macerated and extracted with acetone. All extracts were evaporated under reduced pressure and combined to give a crude gum (8.0 g). The extract was separated by VLC on silica gel using a stepped gradient elution petroleum ether− CH2Cl2 (10:0 to 0:10) and CH2Cl2−MeOH (10:0 to 0:10) to give five fractions (Fraction 1 to Fraction 5). Fraction 3 (1:10 Petroleum ether−CH2Cl2) was further separated on a Sephadex LH-20 column to provide five subfractions (Fraction 3-1 to Fraction 3-5). Fraction 3-4 was separated by MPLC and semipreparative HPLC eluted with MeOH−H2O (70:30), to obtain compounds 1 (15.0 mg, tR = 20.5 min) and 2 (5.0 mg, tR = 21.5 min). Fraction 4 (100% CH2Cl2) was further separated on a Sephadex LH-20 column to provide three subfractions (Fraction 4-1 to Fraction 4-3). Fraction 4-2 was separated by semipreparative HPLC eluted with MeOH−H2O (50:50), to obtain compounds 3 (3.5 mg, tR = 13.8 min), 4 (4.0 mg, tR = 15.6 min), and 5 (2.0 mg, tR = 17.9 min). The whole fermentation broth of S. lamellicola HDN13-430 (200 mL) was filtered through cheese cloth to separate the supernatant from the mycelia. The supernatant was extracted with EtOAc, and the mycelia was macerated and extracted with acetone. All extracts were evaporated under reduced pressure to give a crude gum (0.5 g). Compound 1 was separated by MPLC, and semipreparative HPLC eluted with MeOH−H2O (70:30), to obtain compound 1 (5.0 mg, tR = 20.5 min). Saroclide A (1). White powder; [α]20D +120 (c 0.1, MeOH); UV (MeOH) λmax (log ε): 208 (3.4), 240 (3.2) nm; IR (KBr) νmax 3470, 3040, 2968, 2932, 1710, 1596, 1450, 1381, 1378, 775 cm−1; for 1H and 13 C NMR data see Table 1; HRESIMS m/z 441.2390 [M + H]+ (calcd for C25H33N2O5, 441.2384). Saroclide B (2). White powder; [α]20D +150 (c 0.1, MeOH); UV (MeOH) λmax (log ε): 210 (3.3), 244 (3.0) nm; IR (KBr) νmax 3450, 3050, 2928, 2876, 1715, 1676, 1488, 1405, 1374, 765 cm−1; for 1H and 13 C NMR data see Table 1; HRESIMS m/z 441.2395 [M + H]+ (calcd for C25H33N2O5, 441.2384). Cytotoxicity Assays. Cytotoxic activities of 1−5 were evaluated using HeLa (human cervical cancer cell line), BEL-7402 (human hepatocellular carcinoma cell line), HEK-293 (human embryonic kidney cell line), HCT-116 (human colon cancer cell line), and A549 (lung cancer cell line) by MTT or SRB methods,18,19 with doxorubicin as a positive control (IC50 values 0.5, 0.3, 0.08, 0.4, and 0.7 μM respectively). Antibacterial Activity. The test organisms were Escherichia coli, Staphylococcus aureus, Candida albicans, and Bacillus subtilis. Antibacterial assays were carried out by the doubling dilution method as described in the published protocol.20 Chloramphenicol was used as a positive control. Lipid-Lowering Activity. HepG2 cells were cultured in a high glucose DMEM medium containing 10% fetal bovine serum (FBS) at 37 °C and 5% CO2. After reaching 90% confluence, cells were incubated with the indicated concentration of compound (2.5, 5.0, and 10.0 μM) or with simvastatin (10 μM) in high glucose DMEM containing oil acid (OA, 100 μM) for 24 h. The blank group was

incubated with serum-free high glucose DMEM alone. Oil red O staining was performed as previously reported,9a and the intracellular contents of total cholesterol and triglyceride were determined by kits according to manufacturer’s instructions. For cell viability assay, the cells were incubated for 20 h in the presence of 1 after the cell reached confluence. Subsequently, the culture medium was removed and replaced by 100 μL of fresh culture medium containing 10% sterile filtered MTT. After 4 h, the insoluble formazan crystals were dissolved in 100 μL/well isopropanol, and the absorbance was measured at 570 nm, using the 630 nm reading as a reference. The inhibition of growth due to 1 was expressed as a percentage of viable cells in experimental wells relative to blank wells. Preparation and Analysis of L-FDAA Derivatives. Compounds 1 and 2 (1.5 mg) were dissolved in 1.5 mL of 6 M HCl and subsequently heating at 105 °C for 10 h. The reaction mixtures were then concentrated to dryness and redissolved in 400 μL of H2O, respectively. For the derivatizations, 200 μL of the hydrolysate solution were mixed with 100 μL of 0.25 μM L-FDAA in acetone. After addition of 25 μL of 1 M NaHCO3, the mixtures were stirred at 40 °C for 1 h. The reactions were quenched by addition of 100 μL of 2 M HCl. The amino acid standards were derivatized with L-FDAA as previously described. Prior to HPLC-UV analyses the reaction mixtures were diluted with CH3CN−H2O (55:45 + 0.05% TFA). The retention times of the amino acid standard derivatives were as follows (min): LFDAA-L-Pro (32.3), L-FDAA-D-Pro (33.5), L-FDAA-L-Phe (42.3), and L-FDAA-D-Phe (45.5). The HPLC analysis of the hydrolysate L-FDAA derivatives displayed peaks at 32.3/45.5 min for 1 and 33.5/45.5 min for 2. The additional confirmations of the amino acid configurations were accomplished by spiking the hydrolysate derivatives with the amino acid standard derivatives. X-ray Crystallographic Analysis of Compound 1. An optically active white crystal of 1 was obtained in MeOH−H2O. The crystal data were recorded with an Xcalibur Eos Gemini single-crystal diffractometer with Cu Kα radiation (λ = 1.54184 Å). The structures were solved by an audit creation method (SHELXL-97) and refined using SHELXL-97 (Sheldrick 1997). Crystallographic data have been deposited in the Cambridge Crystallographic Data Center with the deposition number CCDC 1016931. A copy of the data can be obtained, free of charge, on application to the Director, CCDC, 12 Union Road, Cambridge CB21EZ, U.K. (fax, +44(0)-1233-336033; email, [email protected]). Crystal Data for 1. Colorless (block), orthorhombic, space group P212121, a = 9.2128(4) Å, b = 13.0361(5) Å, c = 20.7294(8) Å, V = 2489.59(18) Å3, Z = 4, μ(Cu Kα) = 3.9970, T = 293(2), and F(000) = 940, crystal size 0.08 × 0.07 × 0.07 mm3; Rint (R factor for symmetryequivalent intensities) = 0.0642. Flack parameter = −0.1(5).

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.7b00644. The MS and NMR spectra, Marfey’s experimental data of 1 and 2 (PDF) Crystallographic data for compound 1 (CIF)

■

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (D.L.). Tel: 0086-532-82031619. Fax: 0086-532-82033054. *E-mail: [email protected] (P.G.). Tel: 0086-532-82031619. Fax: 0086-532-82033054. ORCID

Dehai Li: 0000-0002-7191-2002 Author Contributions ⊥

D

W.G. and S.W. contributed equally to this paper. DOI: 10.1021/acs.jnatprod.7b00644 J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products

Note

Notes

(17) Colegate, S. M.; Molyneux, R. J. Bioactive Natural Products: Detection, Isolation, and Structural Determination, 2nd ed.; Taylor and Francis: Boca Raton, FL, 2008; pp 209−219. (18) Mosmann, T. J. Immunol. Methods 1983, 65, 55−63. (19) Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, J.; Vistica, D.; Warren, J. T.; Bokesch, H.; Kenney, S.; Boyd, M. R. J. Natl. Cancer Inst. 1990, 82, 1107−1112. (20) Winkelmann, K.; Heilmann, J.; Zerbe, O.; Rali, T.; Sticher, O. J. Nat. Prod. 2000, 63, 104−108.

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This work was financially supported by the National Natural Science Foundation of China (21372208, and 41676127), NSFC-Shandong Joint Fund for Marine Science Research Centers (U1606403), the Scientific and Technological Innovation Project (2015ASKJ02), AoShan Talents Program Supported by Qingdao National Laboratory for Marine Science and Technology (2015ASTP-ES09), Shandong province key research and development program (2016GSF201204), and Fundamental Research Funds for the Central Universities (201564026).

■

REFERENCES

(1) Sarabia, F.; Chammaa, S.; Ruiz, A. S.; Ortiz, L. M.; Herrera, F.; Jorge, L. Curr. Med. Chem. 2004, 11, 1309−1332. (2) Guo, J.; Zhu, C.; Zhang, C.; Chu, Y.; Wang, Y.; Zhang, J.; Wu, D.; Zhang, K.; Niu, X. J. Am. Chem. Soc. 2012, 134, 20306−20309. (3) Marrakchi, R.; Chouchani, C.; Poschmann, J.; Andreev, E.; Cherif, M.; Ramotar, D. Biochem. Cell Biol. 2013, 91, 123−130. (4) (a) Yao, Y.; Cheng, Z.; Ye, H.; Xie, Y.; He, J.; Tang, M.; Shen, T.; Wang, J.; Zhou, Y.; Lu, Z. J. Sep. Sci. 2010, 33, 1331−1337. (b) Rogalska, A.; Gajek, A.; Marczak, A. Toxicol. In Vitro 2014, 28, 675−683. (5) Jin, Y.; Gill, S.; Kirchhoff, P.; Wan, B.; Franzblau, S.; Garcia, G.; Showalter, H. Bioorg. Med. Chem. Lett. 2011, 21, 6094−6099. (6) Li, D.; Carr, G.; Zhang, Y.; Williams, D. E.; Amlani, A.; Bottriell, H.; Mui, A. L.-F.; Andersen, R. J. J. Nat. Prod. 2011, 74, 1093−1099. (7) (a) Gerwick, W. H.; Tan, L.; Sitachitta, N. The Alkaloids; Academic Press: San Diego, 2001; Vol. 57, pp 75−184. (b) Ramaswamy, A. V.; Sorrels, C. M.; Gerwick, W. H. J. Nat. Prod. 2007, 70, 1977−1986. (8) (a) Finking, R.; Marahiel, M. Annu. Rev. Microbiol. 2004, 58, 453−488. (b) Weissman, K. J. Philos. Trans. R. Soc., A 2004, 362, 2671−2690. (9) (a) Li, L.; Li, D.; Luan, Y.; Gu, Q.; Zhu, T. J. Nat. Prod. 2012, 75, 920−927. (b) Wu, G.; Ma, H.; Zhu, T.; Li, J.; Gu, Q.; Li, D. Tetrahedron 2012, 68, 9745−9749. (c) Wu, G.; Lin, A.; Gu, Q.; Zhu, T.; Li, D. Mar. Drugs 2013, 11, 1399−1408. (d) Gao, H.; Zhu, T.; Li, D.; Gu, Q.; Liu, W. Arch. Pharmacal Res. 2013, 36, 952−956. (e) Gao, H.; Guo, W.; Wang, Q.; Zhang, L.; Zhu, M.; Zhu, T.; Gu, Q.; Wang, W.; Li, D. Bioorg. Med. Chem. Lett. 2013, 23, 1776−1778. (f) Peng, J.; Lin, T.; Wang, W.; Xin, Z.; Zhu, T.; Gu, Q.; Li, D. J. Nat. Prod. 2013, 76, 1133−1140. (g) Lin, A. Q.; Wu, G. W.; Gu, Q. Q.; Zhu, T. J.; Li, D. H. Arch. Pharmacal Res. 2014, 37, 839−844. (h) Zhou, H.; Li, L.; Wang, W.; Che, Q.; Li, D.; Gu, Q.; Zhu, T. J. Nat. Prod. 2015, 78, 1442−1445. (10) Mori, K.; Otsuka, T.; Oda, M. Tetrahedron 1984, 40, 2929− 2934. (11) Rönsberg, D.; Debbab, A.; Mándi, A.; Wray, V.; Dai, H.; Kurtán, T.; Proksch, P.; Aly, A. H. Tetrahedron Lett. 2013, 54, 3256−3259. (12) Rukachaisirikul, V.; Buadam, S.; Phongpaichit, S. Tetrahedron 2013, 69, 10711−10717. (13) (a) Friedman, M. Chem. Biodiversity 2010, 7, 1491−530. (b) Radkov, A. D.; Moe, L. A. Appl. Microbiol. Biotechnol. 2014, 98, 5363−5374. (c) Ollivaux, C.; Soyez, D.; Toullec, J. Y. J. Pept. Sci. 2014, 20, 595−612. (14) Li, D.; Guo, W.; Li, N.; Gu, Q.; Zhu, T.; Che, Q.; Guo, P. J. Antibiot. 2017, 70, 174. (15) (a) Fujii, K.; Ikai, Y.; Mayumi, T.; Oka, H.; Suzuki, M.; Harada, K. Anal. Chem. 1997, 69, 3346−3352. (b) Fujii, K.; Ikai, Y.; Mayumi, T.; Oka, H.; Suzuki, M.; Harada, K. Anal. Chem. 1997, 69, 5146−5151. (16) (a) Lee, S. T.; Gardner, D. R.; Chang, C.-W. T.; Panter, K. E.; Molyneux, R. J. Phytochem. Anal. 2008, 19, 395−402. (b) Miller, K. A.; Tsukamoto, S.; Williams, R. M. Nat. Chem. 2009, 1, 63−68. E

DOI: 10.1021/acs.jnatprod.7b00644 J. Nat. Prod. XXXX, XXX, XXX−XXX