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RESEARCH FRONT
Contents Vol 68(2)

The Multiple Properties of Gliotoxin and Other Epipolythiodioxopiperazine Metabolites

Paul Waring A D and Christina L. L. Chai B C
+ Author Affiliations
- Author Affiliations

A ANU College, Building 95, The Fulton Muir Building, The Australian National University, Canberra, ACT 0200, Australia.

B Institute of Chemical & Engineering Sciences, A*STAR (Agency for Science, Technology and Research), 8 Biomedical Grove, Neuros#07-01, Singapore 138665.

C Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543.

D Corresponding author. Email: Paul.Waring@anucollege.edu.au




Paul Waring graduated with a B.Sc. (Hons) from the University of Queensland and gained a Ph.D. in 1978 under the supervision of Dr Des Brown. After a post-doctoral appointment in the Robert Robinson Laboratories in Liverpool, UK, Dr Waring returned to the John Curtin School of Medical Research (JCSMR) to study pteridine chemistry in Wilf Armarego's group. During this formative period, he developed an interest in both biochemistry and toxins. Following the discovery of the immunosuppressive effects of gliotoxin in the immunology department of the JCSMR, he was given an opportunity to apply chemical techniques to help unravel the mechanism of action of this unusual metabolite. This was followed by an involvement in the chemistry, biochemistry, and biology of gliotoxin over the next 20 years which extended into studies of apoptotic cell death induced by various toxins. He now teaches a Critical Thinking course at ANU College.


Christina Li Lin Chai obtained her B.Sc. (Hons) from the University of Canterbury, New Zealand, and her Ph.D. in synthetic organic chemistry from the Research School of Chemistry, ANU. She first joined the Chemistry Department at Victoria University of Wellington, New Zealand (1991–1993), then at ANU (1994–2004). The latter was where she met the late Professor Des Brown, mostly in the library while Des was doing his literature searches. Dr Chai moved to Singapore in December 2004, where she headed a research program in organic chemistry in the then newly founded Institute of Chemical and Engineering Sciences at the Agency for Science, Technology and Research (A*STAR). Since August 2011, Dr Chai has held a joint appointment as Associate Professor in the Department of Pharmacy, National University of Singapore, and in the Institute of Chemical and Engineering Sciences, A*STAR. Her research interests are in the areas of medicinal chemistry, green technologies, and synthesis of bioactive compounds and elucidation of their mechanisms.

Australian Journal of Chemistry 68(2) 178-183 https://doi.org/10.1071/CH14482
Submitted: 1 August 2014  Accepted: 10 December 2014   Published: 23 January 2015

Abstract

The bridged disulfide ring of the fungal metabolite gliotoxin presents both synthetic challenges and confers the molecule with a variety of interesting biological activities. This review summarises recent synthetic strategies used to insert the disulfide and polysulfide bridge across the diketopiperazine ring and briefly describes the limited structure–activity data available for this class of molecule which clearly shows the presence of the disulfide bridge dominates their biological activities. The review also covers possible cellular targets of these toxins, the possible role for the disulfide bridge in toxicity and cellular uptake mechanisms, and the nature of the cell death induced by the epipolythiopiperazinedione toxins. The potential role of this simple molecule as a diagnostic marker for invasive aspergillosis is also discussed.


References

[1]  Howard Florey Penicillin Nobel Lecture, 11 December 1945. Available at http://wwwnobelprizeorg/nobel_prizes/medicine/laureates/1945/).

[2]  L. Li, D. Li, Y. Luan, Q. Gu, T. Zhu, J. Nat. Prod. 2012, 75, 920.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XmvV2ntrg%3D&md5=0bbc05799402b4d1817435154c7347b8CAS | 22583079PubMed |

[3]  R. Reategui, J. Rhea, J. Adolphson, K. Waikins, R. Newell, J. Rabenstein, U. Mocek, M. Luche, G. Carr, J. Nat. Prod. 2013, 76, 1523.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXhsVynsrzN&md5=8a4ec4163fe7c165ff72573381b117edCAS | 24050204PubMed |

[4]  G.-Y. Li, B.-G. Li, T. Yang, J.-F. Yan, G.-Y. Liu, G.-L. Zhang, J. Nat. Prod. 2006, 69, 1374.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28XosFart7w%3D&md5=6e3d1f089cae3d6ec4be4a312ded653cCAS | 16989540PubMed |

[5]  R. Weindling, O. H. Emerson, Phytopathology 1936, 26, 1068.
         | 1:CAS:528:DyaA2sXotVGl&md5=04bd173f94880e457ad0b85b2f36823dCAS |

[6]  M. R. Bell, J. R. Johnson, B. S. Wildi, R. B. Woodward, J. Am. Chem. Soc. 1958, 80, 1001.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaG1cXnslakug%3D%3D&md5=d67db16a28486aff1ee24e2e1b7fca6aCAS |

[7]  A. Mullbacher, P. Waring, R. D. Eichner, J. Gen. Microbiol. 1985, 131, 1251.
         | 1:STN:280:DyaL2M3mtlGgsg%3D%3D&md5=405020d03fa350c354fce1c56eaac7edCAS | 2410548PubMed |

[8]  (a) Y. Kishi, S. Nakatsuka, T. Fukuyama, M. Havel, J. Am. Chem. Soc. 1973, 95, 6493.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaE3sXltlOisrk%3D&md5=75acd1bd8a549d1d53affa2d25ceb1e0CAS | 4733402PubMed |
      (b) T. Fukuyama, Y. Kishi, J. Am. Chem. Soc. 1976, 98, 6723.
         | Crossref | GoogleScholarGoogle Scholar |
      (c) T. Fukuyama, S. Nakatsuka, Y. Kishi, Tetrahedron 1981, 37, 2045.
         | Crossref | GoogleScholarGoogle Scholar |

[9]  P. W. Trown, Biochem. Biophys. Res. Commun. 1968, 33, 402.
         | 1:CAS:528:DyaF1MXjslOksA%3D%3D&md5=e9199dcb7f90f61b859618094f3d565dCAS | 5722231PubMed |

[10]  T. Hino, T. Sato, Chem. Pharm. Bull. (Tokyo) 1974, 22, 2866.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaE2MXpsl2qsg%3D%3D&md5=d35668a61c6cb92b6c3888314ee7c94dCAS |

[11]  E. Oehler, H. Poisel, F. Tataruch, U. Schmidt, Chem. Ber. 1972, 105, 635.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaE38Xht1Kqs7Y%3D&md5=3cf3753fba0543ff852b7473e0cd9fa0CAS |

[12]  (a) K. C. Nicolaou, D. Giguere, S. Totokotsopoulos, Y. P. Sun, Angew. Chem. 2012, 51, 728.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXhsF2lurzK&md5=00dcb33cd6aa817b9ecd8ac5cc6a7aeeCAS |
      (b) K. C. Nicolaou, M. Lu, S. Totokotsopoulos, P. Heretsch, D. Giguere, Y. P. Sun, D. Sarlah, T. H. Nguyen, I. C. Wolf, D. F. Smee, C. W. Day, S. Bopp, E. A. Winzeler, J. Am. Chem. Soc. 2012, 134, 17320.
         | Crossref | GoogleScholarGoogle Scholar |

[13]  (a) H. C. Ottenheijm, J. A. Hulshof, R. J. Nivard, J. Org. Chem. 1975, 40, 2147.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaE2MXkvFOhsr4%3D&md5=f814052f168d384f7128adb4c611dc02CAS |
      (b) H. C. Ottenheijm, J. D. Herscheid, G. P. Kerkhoff, T. F. Spande, J. Org. Chem. 1976, 41, 3433.
         | Crossref | GoogleScholarGoogle Scholar |
      (c) H. C. J. Ottenheijm, J. D. M. Herscheid, G. P. C. Kerkhoff, T. F. Spande, J. Org. Chem. 1976, 41, 3433.
         | Crossref | GoogleScholarGoogle Scholar |

[14]  (a) J. Yoshimura, H. Nakamura, K. Matsunari, Y. Sugiyama, Chem. Lett. 1974, 3, 559.
         | Crossref | GoogleScholarGoogle Scholar |
      (b) J. Yoshimura, Y. Sugiyama, K. Matsunari, H. Nakamura, Bull. Chem. Soc. Jpn. 1974, 47, 1215.
         | Crossref | GoogleScholarGoogle Scholar |
      (c) J. Yoshimura, H. Nakamura, K. Matsunari, Bull. Chem. Soc. Jpn. 1975, 48, 605.
         | Crossref | GoogleScholarGoogle Scholar |

[15]  A. Srinivasan, A. J. Kolar, R. K. Olsen, J. Heterocycl. Chem. 1981, 18, 1545.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaL38Xhs1alt7w%3D&md5=0aada25c2a89051f6967cbc5c6ec64b1CAS |

[16]  (a) J. Kim, M. Movassaghi, J. Am. Chem. Soc. 2010, 132, 14376.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXht1Snsr%2FJ&md5=62bb437f138da0f69bfb5375d53714b1CAS | 20866039PubMed |
      (b) N. Boyer, M. Movassaghi, Chem. Sci. 2012, 3, 1798.
         | Crossref | GoogleScholarGoogle Scholar |
      (c) N. Boyer, K. C. Morrison, J. Kim, P. J. Hergenrother, M. Movassaghi, Chem. Sci. 2013, 4, 1646.
         | Crossref | GoogleScholarGoogle Scholar |
      (d) A. Coste, J. Kim, T. C. Adams, M. Movassaghi, Chem. Sci. 2013, 4, 3191.
         | Crossref | GoogleScholarGoogle Scholar |

[17]  (a) J. E. DeLorbe, S. Y. Jabri, S. M. Mennen, L. E. Overman, F. L. Zhang, J. Am. Chem. Soc. 2011, 133, 6549.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXktlOlsrw%3D&md5=1576418e459c22a2a445c5883a9fc091CAS | 21473649PubMed |
      (b) J. E. DeLorbe, D. Horne, R. Jove, S. M. Mennen, S. Nam, F. L. Zhang, L. E. Overman, J. Am. Chem. Soc. 2013, 135, 4117.
         | Crossref | GoogleScholarGoogle Scholar |
      (c) S. Y. Jabri, L. E. Overman, J. Org. Chem. 2013, 78, 8766.
         | Crossref | GoogleScholarGoogle Scholar |

[18]  (a) E. Iwasa, Y. Hamashima, S. Fujishiro, E. Higuchi, A. Ito, M. Yoshida, M. Sodeoka, J. Am. Chem. Soc. 2010, 132, 4078.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXivVOgtbg%3D&md5=e3f508d3caf40e97ecc674102f53a3b6CAS | 20210309PubMed |
      (b) E. Iwasa, Y. Hamashima, S. Fujishiro, D. Hashizume, M. Sodeoka, Tetrahedron 2011, 67, 6587.
         | Crossref | GoogleScholarGoogle Scholar |

[19]  (a) A. E. Aliev, S. T. Hilton, W. B. Motherwell, D. L. Selwood, Tetrahedron Lett. 2006, 47, 2387.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28XitVOjtLk%3D&md5=8dee8b2ba25ac7d73141f7079c414379CAS |
      (b) B. C. Sil, S. T. Hilton, Synlett 2013, 24, 2563.
         | Crossref | GoogleScholarGoogle Scholar |

[20]  (a) D. H. Scharf, T. Heinekamp, N. Remme, P. Hortschansky, A. A. Brakhage, C. Hertweck, Appl. Microbiol. Biotechnol. 2012, 93, 467.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XntlGltw%3D%3D&md5=2d2905a5a6a19a6ef165bd7679b4890cCAS | 22094977PubMed |
      (b) D. H. Scharf, N. Remme, A. Habel, P. Chankhamjon, K. Scherlach, T. Heinekamp, P. Hortschansky, A. A. Brakhage, C. Hertweck, J. Am. Chem. Soc. 2011, 133, 12322.
         | Crossref | GoogleScholarGoogle Scholar |

[21]  D. Greiner, T. Bonaldi, R. Eskeland, E. Roemer, A. Imhof, Nat. Chem. Biol. 2005, 1, 143.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2MXmt1ygsr4%3D&md5=6daefe35aeb4434b841aa052b8d2a740CAS | 16408017PubMed |

[22]  (a) F. L. Cherblanc, K. L. Chapman, R. Brown, M. J. Fuchter, Nat. Chem. Biol. 2013, 9, 136.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXis1ajurs%3D&md5=3c84077b25041ba4fc7722b0a942b7cbCAS | 23416387PubMed |
      (b) F. L. Cherblanc, K. L. Chapman, J. Reid, A. J. Borg, S. Sundriyal, L. Alcazar-Fuoli, E. Bignell, M. Demetriades, C. J. Schofield, P. A. DiMaggio, R. Brown, M. J. Fuchter, J. Med. Chem. 2013, 56, 8616.
         | Crossref | GoogleScholarGoogle Scholar |
      (c) S. Fujishiro, K. Dodo, E. Iwasa, Y. Teng, Y. Sohtome, Y. Hamashima, A. Ito, M. Yoshida, M. Sodeoka, Bioorg. Med. Chem. Lett. 2013, 23, 733.
         | Crossref | GoogleScholarGoogle Scholar |

[23]  J. D. Tibodeau, L. M. Benson, C. R. Isham, W. G. Owen, K. C. Bible, Antioxid. Redox Signaling 2009, 11, 1097.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXkt1Chs7Y%3D&md5=6bae9d089f9a4d4d308ff85a4420c98bCAS |

[24]  H. S. Choi, J. S. Shim, J. A. Kim, S. W. Kang, H. J. Kwon, Biochem. Biophys. Res. Commun. 2007, 359, 523.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXmsFyksrw%3D&md5=1f42072940e98599b03183d2dc4f3284CAS | 17544368PubMed |

[25]  P. W. Trown, J. A. Bilello, Antimicrob. Agents Chemother. 1972, 2, 261.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaE3sXpt12ksg%3D%3D&md5=b37077601d6d88b670379ad381c1d784CAS | 4670497PubMed |

[26]  P. Waring, A. Sjaarda, Q. H. Lin, Biochem. Pharmacol. 1995, 49, 1195.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2MXlvVGhsbk%3D&md5=ae62f492fe6cb651834aa70988ad7bc8CAS | 7539267PubMed |

[27]  H. L. Pahl, B. Krauss, K. Schulze-Osthoff, T. Decker, E. B.-M. Traencker, M. Vogt, C. Myers, T. Parks, P. Waring, A. Mullbacher, A.-P. Czernilofsky, P. A. Baeuerle, J. Exp. Med. 1996, 183, 1829.
         | Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaK283mtFKrsA%3D%3D&md5=9da51ba7bc7bf5a6cf6958635f4ee09fCAS | 8666939PubMed |

[28]  K. L. Moerman, C. L. L. Chai, P. Waring, Toxicol. Appl. Pharmacol. 2003, 190, 232.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3sXlvFOrsrs%3D&md5=ad683fe5bab057ce049fcb860bdc7022CAS | 12902194PubMed |

[29]  A. Mullbacher, A. F. Moreland, P. Waring, A. Sjaarda, R. D. Eichner, Transplantation 1988, 46, 120.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaL1cXltVCgurk%3D&md5=1915e1b7172640960ec396ef7a00611cCAS | 2455943PubMed |

[30]  S. J. Riedl, G. S. Salvesen, Nat. Rev. Mol. Cell Biol. 2007, 8, 405.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXksFSjsr4%3D&md5=4750a636b85f97ae1857673d307779cbCAS | 17377525PubMed |

[31]  P. Waring, T. Khan, A. Sjaarda, J. Biol. Chem. 1997, 272, 17929.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2sXkslKgu7k%3D&md5=184952f847c497a89fb8eb19cdf27b3aCAS | 9218417PubMed |

[32]  A. Geissler, F. Haun, D. O. Frank, K. Wieland, M. M. Simon, M. Idzko, R. J. Davis, U. Maurer, C. Borner, Cell Death Differ. 2013, 20, 1317.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXhsVeis7nJ&md5=23d870c50d2c3d9f34028290d03a8a75CAS | 23832115PubMed |

[33]  A. M. Hurne, C. L. L. Chai, K. Moerman, P. Waring, J. Biol. Chem. 2002, 277, 31631.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD38XmslOqtrY%3D&md5=6d33d658c2a0c9544404fefc1fcd6060CAS | 12063251PubMed |

[34]  R. D. Eichner, P. Waring, A. M. Geue, A. W. Braithwaite, A. Mullbacher, J. Biol. Chem. 1988, 263, 3772.
         | 1:CAS:528:DyaL1cXhvVWltbs%3D&md5=9072bdfc8ec5b15cdb775b11b77cbea3CAS | 2450088PubMed |

[35]  Y. K. Suen, K. P. Fung, C. Y. Lee, S. K. Kong, Free Radical Res. 2001, 35, 1.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXlslKmsb4%3D&md5=1557868fd95216cd7f817a9e224c3242CAS |

[36]  D. W. Denning, Clin. Infect. Dis. 1998, 26, 781.
         | Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaK1c3isFKnsA%3D%3D&md5=341b794415e304b91e26f6cd7b6698d1CAS | 9564455PubMed |

[37]  R. E. Lewis, N. P. Wiederhold, J. Chi, X. Y. Han, K. V. Komanduri, D. P. Kontoyiannis, R. A. Prince, Infect. Immun. 2005, 73, 635.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2MXisF2jtg%3D%3D&md5=956e389cf6160b46574d5949e82d31baCAS | 15618207PubMed |

[38]  J. W. Bok, D. Chung, A. Balajee, K. A. Marr, D. Andes, K. F. Nielsen, J. C. Frisvad, K. A. Kirby, N. P. Keller, Infect. Immun. 2006, 74, 6761.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28XhtlWgs7jE&md5=8775849efd3e1693daefb26a76a888cbCAS | 17030582PubMed |

[39]  P. Waring, N. Newcombe, M. Edel, Q. H. Lin, H. Jiang, A. Sjaarda, T. Piva, A. Mullbacher, Toxicon 1994, 32, 491.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2cXktVaqurw%3D&md5=d2d3b62c3d3f6bbf6d596920ef66637dCAS | 7519793PubMed |

[40]  P. H. Bernardo, N. Brasch, C. L. L. Chai, P. Waring, J. Biol. Chem. 2003, 278, 46549.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3sXovFKlu7w%3D&md5=429c5c2eb86fb3f60cdd057d6b956d4cCAS | 12947114PubMed |

[41]  J. P. Beaver, P. Waring, Eur. J. Cell Biol. 1995, 68, 47.
         | 1:CAS:528:DyaK2MXoslKlsbc%3D&md5=7e7d62a245a8a9db283b176b8a5cc809CAS | 8549589PubMed |