Next Article in Journal
High-Throughput Identification of Antimicrobial Peptides from Amphibious Mudskippers
Previous Article in Journal
Antimicrobial Peptide Epinecidin-1 Modulates MyD88 Protein Levels via the Proteasome Degradation Pathway
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Short Note

Aspersymmetide A, a New Centrosymmetric Cyclohexapeptide from the Marine-Derived Fungus Aspergillus versicolor

1
Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China
2
Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266200, China
3
State Key Laboratory for Marine Corrosion and Protection, Luoyang Ship Material Research (LSMRI), Qingdao 266061, China
4
Syngenta, Jealott’s Hill International Research Centre, Bracknell RG42 6EY, Berkshire, UK
5
Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao 266003, China
*
Authors to whom correspondence should be addressed.
Mar. Drugs 2017, 15(11), 363; https://doi.org/10.3390/md15110363
Submission received: 10 October 2017 / Revised: 31 October 2017 / Accepted: 13 November 2017 / Published: 22 November 2017

Abstract

:
A new centrosymmetric cyclohexapeptide, aspersymmetide A (1), together with a known peptide, asperphenamate (2), was isolated from the fungus Aspergillus versicolor isolated from a gorgonian coral Carijoa sp., collected from the South China Sea. The chemical structure of 1 was elucidated by analyzing its NMR spectroscopy and MS spectrometry data, and the absolute configurations of the amino acids of 1 were determined by Marfey’s method and UPLC-MS analysis of the hydrolysate. Aspersymmetide A (1) represents the first example of marine-derived centrosymmetric cyclohexapeptide. Moreover, 1 exhibited weak cytotoxicity against NCI-H292 and A431 cell lines at the concentration of 10 μM.

1. Introduction

Marine-derived peptides with a hybrid biosynthetic pathway, non-ribosomal peptide synthetases (NRPSs) and polyketide synthetases (PKSs), always show diverse chemicals and activities [1,2,3]. These peptides provide many prophylactic and curative medicinal drugs with wide bioactivities such as antimalarial, antitumor, antimicrobial, antiviral, and cardioprotective actions [4,5,6]. Efforts by many research groups focusing on hybrid peptides from marine organisms have been rewarded by the discoveries of novel and bioactive compounds, and some of them have been clinically studied and approved by FDA for disease treatments. For example, the linear peptides E7974 [7], ASG-5ME [8], SGN-75 [9], and CDX-011 [10], cyclic peptide elisidepsin [11], and aplidine [12] are anticancer agents within Stages I–III clinical trials. Besides, SGN-35 [13] and ziconotide [14,15], semi-synthetic and natural peptides for the treatment of cancer and pain, respectively, have been approved by FDA. It has been illustrated that marine-derived peptides with NRPS/PKS biosynthetic pathway may have the great potential as lead compounds for drug development.
During our research on bioactive metabolites of marine organisms collected from the South China Sea, several bioactive peptides have been isolated from the fungi derived from corals [16,17,18,19]. Recently, chemical investigation of the culture of marine-derived fungus Aspergillus versicolor (TA01-14) isolated from a gorgonian Carijoa sp. resulted in the isolation of a new centrally symmetrical NRPS/PKS-derived cyclohexapeptide, aspersymmetide A (1), and a known peptide, asperphenamate (2) [20] (Figure 1). Herein, we report the isolation, structure elucidation, and biological evaluation of these compounds.

2. Results and Discussion

Aspersymmetide A (1) was obtained as a white powder. (+)-HRESIMS of 1 gave [M + H]+ and [M + Na]+ at m/z 727.3245 and 749.3062, respectively, indicating a molecular formula of C42H42N6O6 with 25 degrees of unsaturation. The 1H NMR spectrum (Table 1) exhibited two amide (NH) protons at δH 12.23 and 9.10, two α-protons of amino acids at δH 5.24 and 4.47, one 1,2-disubstituted benzene ring and one mono-substituted benzene ring (δH 6.83–7.89). The 13C NMR spectrum revealed the presence of three amide carbonyls at δC 169.8, 168.4, and 167.1, twelve aromatic carbons at δC 140.2, 138.3, 132.0, 129.6 (2C), 127.6 (2C), 127.5, 125.8. 121.2, 117.9, and 115.1, and three nitrogen-bearing carbons at δC 60.5, 51.6, and 46.7.
Detailed analysis of 1D and 2D NMR data led to the identification of three units including a proline (Pro.), a phenylalanine (Phe.), and an anthranilic acid (AA) (Figure 2a). However, these three units only were attributed to be half of the proposed molecular formula. It suggested that 1 should be a symmetrical dimer. The HMBC correlations were used to connect the residues in 1. The correlations [Phe-NH→AA-CO] and [AA-NH→Pro-CO] revealed the half sequence of CO-Phe-NH→CO-AA-NH→CO-Pro-N (Figure 2). The [Pro-α-H→Phe-CO] connected the two half sequences to establish the whole cyclic structure, cyclo-[CO-Phe–AA–Pro–Phe–AA–Pro-N]. Additional evidence confirmed the structure of 1 on the basis of the ESI MS2 experiments with neutral losses (Figure 3 and Figure S14). Thus, the planar structure of 1 was determined as shown in Figure 2b.
The absolute configurations of the amino acids in 1 were determined by UPLC-MS analysis of the acid hydrolysate derivatized with Marfey’s reagent (Nα-(2,4-dinitro-5-fluorophenyl)-l-alalinamide, l-FDAA) [21]. The retention times and negative ESIMS indicated the presence of l-Pro and l-Phe in 1 (see Experimental and Figure S16). Thus, the absolute configuration of 1 was determined as shown in Figure 1. These structural features revealed that aspersymmetide A (1) is a centrally symmetric cyclohexapeptide.
Centrosymmetric cyclopeptides (CSCs) are an important class of peptides that always show diverse bioactivities, such as the enniatins [22] with antibiotic, antifungal, antiinsectan, and cytotoxic activities, and PF1022 [23] with anthelmintic activity. Particularly, fusafungine [24], a mixture of enniatins, has been an active agent used in antibiotics for treatment of nasal and throat infection; emodepdide, the bis-para morpholino-PF1022A, has been introduced into the market as a broad spectrum anthelmintic [25]. A literature survey revealed that the majority of CSCs are synthetic [26,27,28,29], while only a few have been found in natural sources, including cyclohexadepsipeptides (310) [22,30,31,32,33,34,35,36,37,38,39,40] and cyclooctadepsipeptides (1114) [25,34,41,42,43,44] (Table 2, Figure S17). Compounds 313 were obtained from terrestrial microorganisms, and 14 was isolated from the marine-derived bacterium Micromonospora sp. aspersymmetide A (1) represents the first example of centrally symmetric cyclohexapeptide from marine organisms.
Aspersymmetide A (1) was evaluated for brine shrimp lethality against Artemia salina, for cytotoxicity against the human breast cancer (MCF-7), human pulmonary carcinoma (NCI-H292), and human skin squamous carcinoma (A-431) cell lines, for antibacterial activity against Staphylococcus albus and Escherichia coli, for antiviral activity against the human cytomegalovirus (HCMV) and herpes simplex virus (HSV-1), and for enzymic inhibition toward acetyl cholinesterase (AChE), Top I, and α-glucosacharase. It displayed weak cytotoxicity against NCI-H292 and A431 cells with an inhibition ratio of 53.84% and 63.62% at a concentration of 10 μM (adriamycin, 1 μM, 93.36% and 91.00%). However, 1 was inactive in other bioassays.

3. Materials and Methods

3.1. General Experimental Procedures

Optical rotations were measured on a JASCO P-1020 digital polarimeter (JASCO Ltd., Tokyo, Japan). IR spectra were recorded on a Nicolet-Nexus-470 spectrometer (Perkin Elmer Ltd., Boston, MA, USA) using KBr pellets. NMR spectra were recorded on a JEOL JEM-ECP NMR spectrometer (JEOL Ltd., Tokyo, Japan; 500 MHz for 1H and 125 MHz for 13C), using TMS as internal standard. The ESIMS spectra were obtained from a Micromass Q-TOF spectrometer (Waters Ltd., Boston, MA, USA). Semi-preparative HPLC was performed on a Hitachi L-2000 system (Hitachi Ltd., Tokyo, Japan) using a C18 column (Kromasil (Eka Ltd., Bohus, Sweden) 250 × 10 mm, 5 μm, 2.0 mL/min). UPLC-MS was performed on Waters UPLC® system (Waters Ltd., Boston, MA, USA) using a C18 column (ACQUITY UPLC® (Waters Ltd., Boston, MA, USA) BEH C18, 2.1 × 50 mm, 1.7 μm; 0.5 mL/min) and ACQUITY QDa ESIMS scan from 150 to 1000 Da. Silica gel (Qingdao Haiyang Chemical Group Co., Qingdao, China; 200–300 mesh), octadecylsilyl silica gel (YMC Co., Ltd., Tokyo, Japan; 45–60 μm), and Sephadex LH-20 (GE Ltd., Hartford, CT, USA) were used for column chromatography (CC). Precoated silica gel plates (Yantai Zhifu Chemical Group Co., Yantai, China; G60, F-254) were used for thin layer chromatography.

3.2. Fungal Material

The fungus Aspergillus versicolor (TA01-14) was isolated from a gorgonian Carijoa sp. (GX-WZ-2010001) collected from the Weizhou coral reefs in the South China Sea in April 2010. The strain was deposited at the Key Laboratory of Marine Drugs, the Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China, with the Genbank (NCBI) accession number KP759287.

3.3. Fermentation, Extraction, and Isolation

The fungus was cultured on rice solid medium (fifty 1000 mL Erlenmeyer flasks, each containing 50 g of rice and 50 mL of sea water) at room temperature. After 60 days of cultivation, the fermented rice substrate was extracted three times with ethyl acetate (EtOAc) (200 mL per flask) to give an organic extract (10 g). The extract was subjected to a silica gel column chromatography (CC) and eluted by a gradient of petroleum ether (PE)–EtOAc (PE, 100%–0), EtOAc–MeOH (v:v, 9:1), and then MeOH to afford eight fractions (Fr.1–Fr.8) on the basis of TLC analysis. Fr.5 was applied over CC of silica gel with PE–EtOAc (PE, 70%–0) to afford three sub-fractions (Fr.5-1–Fr.5-3). Fr.5-3 was then subjected to Sephadex LH-20 CC and eluted with a mixture of CH2Cl2–MeOH (v:v, 1:1) to obtain two sub-fractions (Fr.5-3-1–Fr.5-3-2). Fr.5-3-1 was then repeatedly separated by silica gel and ODS column chromatography, and then purified by HPLC (MeOH–H2O, 75–25) to afford Compounds 1 (3 mg) and 2 (2 mg).
Aspersymmetide A (1): white powder; [ α ] D 24 −174.2 (c 0.80, MeOH); UV (MeOH) λmax (log ε) 206 (4.01), 227 (3.90), 271 (3.34) nm; IR (KBr) νmax 3441, 1632, and 1399 cm−1; 1H and 13C NMR see Table 1; ESI MS2 (fragmentation of m/z 727.52 [M + H]+) m/z 580.25 [M − Phe + H]+, 511.23 [M − Pro − AA + H]+, 461.22 [M − Phe − AA + H]+, 364.16 [M − Pro − AA − Phe + H]+, 267.11 [M − Pro − AA − Phe − Pro + H]+, 217.10 [M − Phe − AA − Pro − Phe + H]+; HRESIMS m/z 727.3245 [M + H]+, 749.3062 [M + Na]+ (calcd. for C42H43N6O6, 727.3239 [M + H]+, C42H42N6O6Na, 749.3058 [M + Na]+).
The structure of 2 was assigned by spectroscopic method and comparison of the 1H- and 13C-NMR data (see Supplementary Information) with those reported in the literature [20].

3.4. Acid Hydrolysis and Marfey’s Analysis of 1

A solution of 1 (0.5 mg) with HCl (6 M, 1 mL) was hydrolyzed by heating for 20 h at 110 °C. The solution was evaporated to dryness under vacuum and redissolved in H2O (250 μL). The acid hydrolysate solution (50 μL) was treated with 1% solution of l-FDAA (20 μL) in acetone followed by a solution of NaHCO3 (1 M, 10 μL). The mixture was heated at 40 °C for 1 h. The reaction was stopped by HCl (2 M, 5 μL). The standards of amino acids (l-Pro, l/d-Pro, l-Phe, and l/d-Phe) were derivatized with l-FDAA in the same manner as that of 1. All l-FDAA derivatives were analyzed and detected by UPLCMS (ACQUITY UPLC® (Waters Ltd., Boston, MA, USA)) BEH C18, 2.1 × 50 mm, 1.7 μm; solvents: MeCN (A), H2O (0.1% HCOOH) (B); linear gradient: 0–13 min, 5–50% A; 13–15 min, 50–100% A; 15–17 min, 100% A; 17–18 min, 100–5% A; 18–20 min, 5% A; flow rate: 0.5 mL/min; monitor: 190–700 nm; ESI MS scan: 150–1000 Da). Retention times (min) and ESI MS of the amino acid derivatives were recorded as follows: l-FDAA–l-Pro 6.24 min, l-FDAA–d-Pro 6.81 min (m/z 367.1 [M − H]), l-FDAA–l-Phe 8.92 min, l-FDAA–d-Phe 9.99 min (m/z 417.1 [M − H]) (Figure S14).

3.5. Biological Assay

Brine shrimp lethality against Artemia salina was evaluated using the modified Reed-Muench method [45], with doxorubicin as a positive control [46]. Cytotoxic activity was evaluated against the MCF-7, NCI-H292, and A-431 cell lines by the MTT method [47], with adriamycin as a positive control. Antibacterial activity against S. albus and E. coli was evaluated by using 96-well microtiter plates [48], with ciprofloxacin as a positive control. Antiviral activity against HCMV and HSV-1 was evaluated by the cytopathic effect (CPE) inhibition assay by the MTT method [47], with cidofovir and acyclovir as positive controls, respectively. AChE inhibition was determined spectrophotometrically using acetylthiocholine iodide (ATCI) as substrate by modified Ellman method [49], with huperzine A and galantamine hydrobromide as positive controls. Top I inhibiting activity was tested on the basis of DNA relaxation experiment [50], with 10-hydroxy camptothecin (OPT) as a positive control. α-Glucosacharase inhibiting activity was evaluated by the Dewi’s method [51], with acarbose as a positive control.

4. Conclusions

A new centrosymmetric cyclopeptide, aspersymmetide A (1), was obtained from the gorgonian-derived fungal strain Aspergillus versicolor (TA01-14). Compound 1 represents the first example of marine-derived centrosymmetric cyclohexapeptide with weak cytotoxicity.

Supplementary Materials

Supplementary materials according to this paper are available online at www.mdpi.com/1660-3397/15/11/363/s1.

Acknowledgments

We thank Syngenta for the fellowship to X.-M.H. This work was supported by the Outstanding Youth Natural Science Foundation of Shandong Province of China (No. JQ201510), the Program of National Natural Science Foundation of China (Nos. 41376145, 41322037, 41606172 and U1606403), the AoShan Talents Program Supported by the Qingdao National Laboratory for Marine Science and Technology (No. 2015ASTP-ES11), the Research Fund of State Key Laboratory for Marine Corrosion and Protection of Luoyang Ship Material Research Institute (LSMRI) [No. KF160411], and the Taishan Scholars Program, China.

Author Contributions

Xue-Mei Hou contributes to extraction, isolation, identification, and manuscript preparation; Ya-Hui Zhang and Ji-Yong Zheng contribute to bioactivity tests; Yang Hai contributes to supplementary data preparation; Chang-Yun Wang, Chang-Lun Shao, and Yu-Cheng Gu are the project leaders organizing and guiding the experiments and manuscript writing.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Donadio, S.; Monciardini, P.; Sosio, M. Polyketide synthases and nonribosomal peptide synthetases: The emerging view from bacterial genomics. Nat. Prod. Rep. 2007, 24, 1073–1109. [Google Scholar] [CrossRef] [PubMed]
  2. Russell, J.C. Polyketides, proteins and genes in fungi: Programmed nano-machines begin to reveal their secrets. Org. Biomol. Chem. 2007, 5, 2010–2026. [Google Scholar]
  3. Fischbach, M.A.; Walsh, C.T. Assembly-line enzymology for polyketide and nonribosomal peptide antibiotics: Logic, machinery, and mechanisms. Chem. Rev. 2006, 106, 3468–3496. [Google Scholar] [CrossRef] [PubMed]
  4. Molinski, T.F.; Dalisay, D.S.; Lievens, S.L.; Saludes, J.P. Drug development from marine natural products. Nat. Rev. Drug Discov. 2009, 8, 69–85. [Google Scholar] [CrossRef] [PubMed]
  5. Lamberth, C. Naturally occurring amino acid derivatives with herbicidal, fungicidal or insecticidal activity. Amino Acids 2016, 48, 929–940. [Google Scholar] [CrossRef] [PubMed]
  6. Liu, S.X.; Gu, W.X.; Lo, D.; Ding, X.Z.; Ujiki, M.; Adrian, T.E.; Soff, G.A.; Silverman, R.B. N-Methylsansalvamide A peptide analogues, potent new antitumor agents. J. Med. Chem. 2005, 48, 3630–3638. [Google Scholar] [CrossRef] [PubMed]
  7. Rocha-Lima, C.M.; Bayraktar, S.; MacIntyre, J.; Raez, L.; Flores, A.M.; Ferrell, A.; Rubin, E.H.; Poplin, E.A.; Tan, A.R.; Lucarelli, A.; et al. A phase 1 trial of E7974 administered on day 1 of a 21-day cycle in patients with advanced solid tumors. Cancer 2012, 118, 4262–4270. [Google Scholar] [CrossRef] [PubMed]
  8. Mattie, M.; Raitano, A.; Morrison, K.; Morrison, K.; An, Z.; Capo, L.; Verlinsky, A.; Leavitt, M.; Ou, J.; Nadell, R.; et al. The discovery and preclinical development of ASG-5ME, an antibody-drug conjugate targeting SLC44A4-positive epithelial tumors including pancreatic and prostate cancer. Mol. Cancer Ther. 2016, 15, 2679–2687. [Google Scholar] [CrossRef] [PubMed]
  9. Tannir, N.M.; Forero-Torres, A.; Ramchandren, R.; Pal, S.K.; Ansell, S.M.; Infante, J.R.; de Vos, S.; Hamlin, P.A.; Kim, S.K.; Whiting, N.C.; et al. Phase I dose-escalation study of SGN-75 in patients with CD70-positive relapsed/refractory non-Hodgkin lymphoma or metastatic renal cell carcinoma. Investig. New Drugs 2014, 32, 1246–1257. [Google Scholar] [CrossRef] [PubMed]
  10. Kolb, E.A.; Gorlick, R.; Billups, C.A.; Hawthorne, T.; Kurmasheva, R.T.; Houghton, P.J.; Smith, M.A. Initial testing (stage 1) of glembatumumab vedotin (CDX-011) by the pediatric preclinical testing program. Pediatr. Blood Cancer 2014, 61, 1816–1821. [Google Scholar] [CrossRef] [PubMed]
  11. Petty, R.; Anthoney, A.; Metges, J.P.; Alsina, M.; Goncalves, A.; Brown, J.; Montagut, C.; Gunzer, K.; Laus, G.; Iglesias Dios, J.L.; et al. Phase Ib/II study of elisidepsin in metastatic or advanced gastroesophageal cancer (IMAGE trial). Cancer Chemother. Pharm. 2016, 77, 819–827. [Google Scholar] [CrossRef] [PubMed]
  12. Barboza, N.M.; Medina, D.J.; Budak-Alpdogan, T.; Aracil, M.; Jimeno, J.M.; Bertino, J.R.; Banerjee, D. Plitidepsin (Aplidin) is a potent inhibitor of diffuse large cell and Burkitt lymphoma and is synergistic with rituximab. Cancer Biol. Ther. 2012, 13, 114–122. [Google Scholar] [CrossRef] [PubMed]
  13. Katz, J.; Janik, J.E.; Younes, A. Brentuximab Vedotin (SGN-35). Clin. Cancer Res. 2011, 17, 6428–6436. [Google Scholar] [CrossRef] [PubMed]
  14. Teichert, R.W.; Olivera, B.M. Natural products and ion channel pharmacology. Future Med. Chem. 2010, 2, 731–744. [Google Scholar] [CrossRef] [PubMed]
  15. Daly, N.L.; Craik, D.J. Conopeptides as novel options for pain management. Drugs Future 2011, 36, 25–32. [Google Scholar] [CrossRef]
  16. Chen, M.; Shao, C.L.; Fu, X.M.; Xu, R.F.; Zheng, J.J.; Zhao, D.L.; She, Z.G.; Wang, C.Y. Bioactive indole alkaloids and phenyl ether derivatives from a marine-derived Aspergillus sp. Fungus. J. Nat. Prod. 2013, 76, 547–553. [Google Scholar] [CrossRef] [PubMed]
  17. Shao, C.L.; Xu, R.F.; Wang, C.Y.; Qian, P.Y.; Wang, K.L.; Wei, M.Y. Potent Antifouling marine dihydroquinolin-2(1H)-one-containing alkaloids from the gorgonian coral-derived fungus Scopulariopsis sp. Mar. Biotechnol. 2015, 17, 408–415. [Google Scholar] [CrossRef] [PubMed]
  18. Zheng, C.J.; Shao, C.L.; Wu, L.Y.; Chen, M.; Wang, K.L.; Zhao, D.L.; Sun, X.P.; Chen, G.Y.; Wang, C.Y. Bioactive phenylalanine derivatives and cytochalasins from the soft coral-derived fungus, Aspergillus elegans. Mar. Drugs 2013, 11, 2054–2068. [Google Scholar] [CrossRef] [PubMed]
  19. Chen, M.; Shao, C.L.; Fu, X.M.; Kong, C.J.; She, Z.G.; Wang, C.Y. Lumazine peptides penilumamides B-D and the cyclic pentapeptide asperpeptide A from a gorgonian-derived Aspergillus sp. fungus. J. Nat. Prod. 2014, 77, 1601–1606. [Google Scholar] [CrossRef] [PubMed]
  20. Chang, R.J.; Wang, C.H.; Zeng, Q.; Guan, B.; Zhang, W.D.; Jin, H.Z. Chemical constituents of the stems of Celastrus rugosus. Arch. Pharm. Res. 2013, 36, 1291–1301. [Google Scholar] [CrossRef] [PubMed]
  21. Marfey, P. Determination of d-amino acids. II. Use of a bifunctional reagent, 1,5-difluoro-2,4-dinitrobenzene. Carlsberg Res. Commun. 1984, 49, 591–596. [Google Scholar] [CrossRef]
  22. Sy-Cordero, A.A.; Pearce, C.J.; Oberlies, N.H. Revisiting the enniatins: A review of their isolation, biosynthesis, structure determination and biological activities. J. Antibiot. 2012, 65, 541–549. [Google Scholar] [CrossRef] [PubMed]
  23. Sakanaka, O.; Okada, Y.; Ohyama, M.; Matsumoto, M.; Takahashi, M.; Murai, Y.; Iinuma, K.; Harder, A.; Mencke, N. Novel Cyclic Depsipeptide PF1022A Derivatives. Patent WO97/11064, 27 March 1997. [Google Scholar]
  24. European Food Safety Authority (EFSA). Scientific opinion on the risks to human and animal health related to the presence of beauvericin and enniatins in food and feed. EFSA J. 2014, 12, 3802. [Google Scholar]
  25. Sasaki, T.; Takagi, M.; Yaguchi, T.; Miyadoh, S.; Okada, T.; Koyama, M. A new anthelmintic cyclodepsipeptide, PF1022A. J. Antibiot. 1992, 45, 692–697. [Google Scholar] [CrossRef] [PubMed]
  26. Madison, V.; Deber, C.M.; Blout, E.R. Cyclic peptides. 17. Metal and amino acid complexes of cyclo(Pro-Gly)4 and analogs studied by nuclear magnetic resonance and circular dichroism. J. Am. Chem. Soc. 1977, 99, 4788–4798. [Google Scholar] [CrossRef] [PubMed]
  27. Mizuno, H.; Lee, S.; Nakamura, H.; Kato, T.; Go, N.; Izumiya, N. Conformational and energy analyses of proline-containing model peptides for β-turn. Peptide Chem. 1984, 21, 145–150. [Google Scholar]
  28. Kessler, H.; Bats, J.W.; Griesinger, C.; Koll, S.; Will, M.; Wagner, K. Peptide conformations. 46. Conformational analysis of a superpotent cytoprotective cyclic somatostatin analog. J. Am. Chem. Soc. 1988, 110, 1033–1049. [Google Scholar] [CrossRef]
  29. Ishizu, T.; Fujii, A.; Noguchi, S. Conformational studies of cyclo(l-Phe-l-Pro-Gly-l-Pro)2 by carbon-13 nuclear magnetic resonance. Chem. Pharm. Bull. 1991, 39, 1617–1619. [Google Scholar] [CrossRef] [PubMed]
  30. Gaumann, E.; Roth, S.; Ettlinger, L.; Plattner, P.A.; Nager, U. Enniatin, a new antibiotic active against Mycobacteria. Experientia 1947, 3, 202–203. [Google Scholar] [PubMed]
  31. Blais, L.A.; Apsimon, J.W.; Blackwell, B.A.; Greenhalgh, R.; Miller, J.D. Isolation and characterization of enniatins from Fusarium avenaceum DAOM 196490. Can. J. Chem. 1992, 70, 1281–1287. [Google Scholar] [CrossRef]
  32. Supothina, S.; Isaka, M.; Kirtikara, K.; Tanticharoen, M.; Thebtaranonth, Y. Enniatin production by the entomopathogenic fungus Verticillium hemipterigenum BCC 1449. J. Antibiot. 2004, 57, 732–738. [Google Scholar] [CrossRef] [PubMed]
  33. Song, H.H.; Ahn, J.H.; Lim, Y.H.; Lee, C. Analysis of beauvericin and unusual enniatins co-produced by Fusarium oxysporum fb1501 (kfcc 11363p). J. Microbiol. Biotechnol. 2006, 16, 1111–1119. [Google Scholar]
  34. Ohshiro, T.; Matsudo, D.; Kazuhiro, T.; Uchida, R.; Nonaka, K.; Masuma, R.; Tomada, H. New verticilides, inhibitors of acyl-CoA:cholesterol acyltransferase, produced by Verticillium sp. FKI-2679. J. Antibiot. 2012, 65, 255–262. [Google Scholar] [CrossRef] [PubMed]
  35. Left, J.E.; Schröder, D.R.; Krishan, B.S.; Matron, J.A. Himastatin, a new antitumor antibiotic from Streptomyces hygroscopicus. II. Isolation and characterization. J. Antibiot. 1990, 43, 961–966. [Google Scholar]
  36. Kamenecka, T.M.; Danishefsky, S.J. Template assembly of polyiodide networks at complexed metal cations: Synthesis and structures of [Pd2Cl2([18]aneN2S4)]1.5I5(I3)2 and [K([15]aneO5)2]I9. Angew. Chem. Int. Ed. 1998, 37, 293–295. [Google Scholar]
  37. Kamenecka, T.M.; Danishefsky, S.J. Discovery through total synthesis: A retrospective on the himastatin problem. Chem. Eur. J. 2001, 7, 41–63. [Google Scholar] [CrossRef]
  38. Zhan, J.; Burns, A.M.; Liu, M.X.; Faeth, S.H.; Gunatilaka, A.A.L. Search for cell motility and angiogenesis inhibitors with potential anticancer activity: Beauvericin and other constituents of two endophytic strains of Fusarium oxysporum. J. Nat. Prod. 2007, 70, 227–232. [Google Scholar] [CrossRef] [PubMed]
  39. Vongvanich, N.; Kittakoop, P.; Isaka, M.; Trakulnaleamsai, S.; Vimuttipong, S.; Tanticharoen, M.; Thebtaranonth, Y. Hirsutellide A, a new antimycobacterial cyclohexadepsipeptide from the entomopathogenic fungus Hirsutella kabayasii. J. Nat. Prod. 2002, 65, 1346–1348. [Google Scholar] [CrossRef] [PubMed]
  40. Dang, T.; Süssmuth, R.D. Bioactive peptide natural products as lead structures for medicinal use. Acc. Chem. Res. 2017, 50, 1566–1576. [Google Scholar] [CrossRef] [PubMed]
  41. Kanaoka, M.; Isogai, A.; Murakoshi, S.; Ichinoe, M.; Suzuki, A.; Tamura, S. Bassianolide, a new insecticidal cyclodepsipeptide from Beauveria bassiana and Verticillium lecanii. Agric. Biol. Chem. 1978, 42, 629–635. [Google Scholar] [CrossRef]
  42. Nakajko, S.; Shimizu, K.; Kometani, A. On the inhibitory mechanism of bassianolide, a cyclodepsipeptides, in acetylcholine-induced contraction in guinea-pig taenia coli. Jpn. J. Pharmacol. 1983, 33, 573–582. [Google Scholar] [CrossRef]
  43. Jirakkakul, J.; Punya, J.; Pongpattanakitshote, S.; Paungmoung, P.; Vorapreeda, N.; Tachaleat, A.; Klomnara, C.; Tanticharoen, M.; Cheevadhanarak, S. Identification of the nonribosomal peptide synthetase gene responsible for bassianolide synthesis in wood-decaying fungus Xylaria sp. BCC1067. Microbiology 2008, 154, 995–1006. [Google Scholar] [CrossRef] [PubMed]
  44. Romero, F.; Espliego, F.; Peérez Baz, J.; García de Quesada, T.; Grávalos, D.; De la Calle, F.; Fernández-Puentes, J.L. Thiocoraline, a new depsipeptide with antitumor activity produced by a marine Micromonospora. I. Taxonomy, fermentation, isolation, and biological activities. J. Antibiot. 1997, 50, 734–737. [Google Scholar] [CrossRef] [PubMed]
  45. Uy, M.M.; Villanueva, M.P. The brine shrimp lethality of the leaf extracts of Piper baccatum Blume and their antioxidant properties. Asian J. Biol. Life Sci. 2015, 4, 179–184. [Google Scholar]
  46. Mou, X.F.; Bian, W.T.; Wang, C.Y.; Shao, C.L. Secondary metabolites isolated from the sea hare Aplysia pulmonica from the South China Sea. Chem. Nat. Compd. 2016, 52, 758–760. [Google Scholar] [CrossRef]
  47. Scudiero, D.A.; Shoemaker, R.H.; Paul, K.D.; Monks, A.; Tierney, S.; Nofziger, T.H.; Currens, M.J.; Seniff, D.; Boyd, M.R. Evaluation of a soluble tetrazolium/formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines. Cancer Res. 1988, 48, 4827–4833. [Google Scholar] [PubMed]
  48. Appendino, G.; Gibbons, S.; Giana, A.; Pagani, A.; Grassi, G.; Stavri, M.; Smith, E.; Rahman, M.M. Antibacterial cannabinoids from Cannabis sativa: A structure-activity study. J. Nat. Prod. 2008, 71, 1427–1430. [Google Scholar] [CrossRef] [PubMed]
  49. Ellman, G.L.; Courtney, K.D.; Andres, V., Jr.; Featherstone, R.M. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol. 1961, 7, 88–95. [Google Scholar] [CrossRef]
  50. Bogurcu, N.; Sevimli-Gur, C.; Ozmen, B.; Bedir, E.; Korkmaz, K.S. ALCAPs induce mitochondrial apoptosis and activate DNA damage response by generating ROS and inhibiting topoisomerase I enzyme activity in K562 leukemia cell line. Biochem. Biophys. Res. Commun. 2011, 409, 738–744. [Google Scholar] [CrossRef] [PubMed]
  51. Dewi, R.T.; Tachibana, S.; Fajriah, S.; Hanafi, M. α-Glucosidase inhibitor compounds from Aspergillus terreus RCC1 and their antioxidant activity. Med. Chem. Res. 2015, 24, 737–743. [Google Scholar] [CrossRef]
Figure 1. Chemical structures of 1 and 2.
Figure 1. Chemical structures of 1 and 2.
Marinedrugs 15 00363 g001
Figure 2. 1H-1H COSY and key HMBC correlations of 1. (a) Residues in 1. (b) The connection of the residues.
Figure 2. 1H-1H COSY and key HMBC correlations of 1. (a) Residues in 1. (b) The connection of the residues.
Marinedrugs 15 00363 g002
Figure 3. ESI MS2 fragment ions for 1.
Figure 3. ESI MS2 fragment ions for 1.
Marinedrugs 15 00363 g003
Table 1. 1H and 13C NMR (500 and 125 MHz, DMSO-d6) of aspersymmetide A (1).
Table 1. 1H and 13C NMR (500 and 125 MHz, DMSO-d6) of aspersymmetide A (1).
PositionδH, Mult. (J in Hz)δC, Type
Pro.1 169.8, C
24.47, d (8.0)60.5, CH
3Ha 2.21, m
Hb 1.72, m
31.4, CH2
4Ha 1.86, m
Hb 1.68, m
20.9, CH2
5Ha 3.52, dd (11.5, 8.5)
Hb 3.40, dd (11.5, 10.2)
46.7, CH2
AA7 167.1, C
8 115.1, C
97.89, d (8.0)127.5, CH
106.83, t (8.0)121.2, CH
116.91, t (8.0)132.0, CH
127.74, d (8.0)117.9, CH
13 140.2, C
14 (NH)12.23, br s
Phe.15 168.4, C
165.24, m51.6, CH
17Ha 3.21, dd (13.6, 5.1)
Hb 2.87, dd (13.6, 9.5)
37.2, CH2
18 138.3, C
19/237.19, d (7.3)129.6, CH
20/227.10, t (7.3)127.6, CH
217.03, t (7.3)125.8, CH
24 (NH)9.10, d (9.0)
Table 2. Natural products of centrosymmetric cyclopeptides (CSCs).
Table 2. Natural products of centrosymmetric cyclopeptides (CSCs).
Compd.Collected SourceBiosynthetic SourceBioactivityReference
Enniatin A (3)FungusFusarium sp.Anti-mycotoxigenic fungi[22,30,31]
Enniatin B (4)Verticillium sp.[22,32]
Enniatin C (5)Verticillium sp.[22,32]
Enniatin MK1688 (6)Fusarium oxysporum[22,33]
Verticilide B1 (7)Verticillium sp.Acyl-CoA:cholesterol acyltransferase inhibition[34]
Himastatin (8)ActinomyceteStreptomyces hygroscopicusCytotoxic activity[35,36,37]
Beauvericin (9)FungusFusarium oxysporumCytotoxic and antiangiogenic activities[38]
Hirsutellide A (10)Hirsutella kobayasiiAntibacterial and antimalarial activities[39]
Verticilide A1 (11)Verticillium sp.Acyl-CoA:cholesterol acyltransferase inhibition[34]
Bassianolide (12)Beauveria bassianaInsecticidal activity[41,42,43]
PF1022A (13)Ascaridia galliAnthelmintic activity[25]
Thiocoraline (14)ActinomyceteMicromonospora sp.Cytotoxic and antimicrobial activities[44]

Share and Cite

MDPI and ACS Style

Hou, X.-M.; Zhang, Y.-H.; Hai, Y.; Zheng, J.-Y.; Gu, Y.-C.; Wang, C.-Y.; Shao, C.-L. Aspersymmetide A, a New Centrosymmetric Cyclohexapeptide from the Marine-Derived Fungus Aspergillus versicolor. Mar. Drugs 2017, 15, 363. https://doi.org/10.3390/md15110363

AMA Style

Hou X-M, Zhang Y-H, Hai Y, Zheng J-Y, Gu Y-C, Wang C-Y, Shao C-L. Aspersymmetide A, a New Centrosymmetric Cyclohexapeptide from the Marine-Derived Fungus Aspergillus versicolor. Marine Drugs. 2017; 15(11):363. https://doi.org/10.3390/md15110363

Chicago/Turabian Style

Hou, Xue-Mei, Ya-Hui Zhang, Yang Hai, Ji-Yong Zheng, Yu-Cheng Gu, Chang-Yun Wang, and Chang-Lun Shao. 2017. "Aspersymmetide A, a New Centrosymmetric Cyclohexapeptide from the Marine-Derived Fungus Aspergillus versicolor" Marine Drugs 15, no. 11: 363. https://doi.org/10.3390/md15110363

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop