Register      Login
Australian Journal of Chemistry Australian Journal of Chemistry Society
An international journal for chemical science
Shopping Cart: ( empty )
You are here: Home > Journals > CH > CH19227
RESEARCH ARTICLE
Contents Vol 73(3)

A Sesquiterpene Isonitrile with a New Tricyclic Skeleton from the Indo-Pacific Nudibranch Phyllidiella pustulosa: Spectroscopic and Computational Studies

Desmond C.-M. Sim A , Natasha L. Hungerford A , Elizabeth H. Krenske A , Gregory K. Pierens B , Katherine T. Andrews C , Tina S. Skinner-Adams C and Mary J. Garson A D
+ Author Affiliations
- Author Affiliations

A School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Qld 4072, Australia.

B Centre for Advanced Imaging, The University of Queensland, St Lucia, Qld 4072, Australia.

C Griffith Institute for Drug Discovery, Griffith University, Nathan, Qld 4111, Australia.

D Corresponding author. Email: m.garson@uq.edu.au

Australian Journal of Chemistry 73(3) 129-136 https://doi.org/10.1071/CH19227
Submitted: 22 May 2019  Accepted: 1 July 2019   Published: 7 August 2019

Abstract

The sesquiterpene isonitrile, 9-isocyanoneoallopupukeanane 1, has been obtained from the Indo-Pacific nudibranch Phyllidiella pustulosa. The structure of 1, which was investigated by extensive NMR experiments, molecular modelling studies, and density functional calculations, has a different arrangement of the tricyclic ring system compared with other isonitrile metabolites isolated from nudibranchs or sponges. The viability of a biosynthetic pathway leading to 1, proposed to involve a series of carbocation rearrangements, is explored in a computational study. Isonitrile 1 exhibited micromolar antimalarial activity when screened against Plasmodium falciparum infected erythrocytes.


References

[1]  C. W. J. Chang, in Progress in the Chemistry of Organic Natural Products (Eds W. Herz, H. Falk, G. W. Kirby, R. E. Moore) 2000, Vol 80, pp. 1–186 (Springer: New York, NY).

[2]  M. J. Garson, J. S. Simpson, Nat. Prod. Rep. 2004, 21, 164.
         | Crossref | GoogleScholarGoogle Scholar | 15039841PubMed |

[3]  J. Emsermann, U. Kauhl, T. Opatz, Mar. Drugs 2016, 14, 16.
         | Crossref | GoogleScholarGoogle Scholar | 26784208PubMed |

[4]  M. J. Schnermann, R. A. Shenvi, Nat. Prod. Rep. 2015, 32, 543.
         | Crossref | GoogleScholarGoogle Scholar | 25514696PubMed |

[5]  F. Le Bideau, M. Kousara, L. Chen, L. Wei, F. Dumas, Chem. Rev. 2017, 117, 6110.
         | Crossref | GoogleScholarGoogle Scholar | 28379015PubMed |

[6]  A. D. Wright, A. McCluskey, M. J. Robertson, K. A. MacGregor, C. P. Gordon, J. Guenther, Org. Biomol. Chem. 2011, 9, 400.
         | Crossref | GoogleScholarGoogle Scholar | 21042642PubMed |

[7]  N. Fusetani, Curr. Org. Chem. 1997, 1, 127.

[8]  K. A. Alvi, L. Tenenbaum, P. Crews, J. Nat. Prod. 1991, 54, 71.
         | Crossref | GoogleScholarGoogle Scholar | 2045823PubMed |

[9]  C. K. Angerhofer, J. M. Pezzuto, G. M. König, A. D. Wright, O. Sticher, J. Nat. Prod. 1992, 55, 1787.
         | Crossref | GoogleScholarGoogle Scholar | 1294700PubMed |

[10]  G. M. König, A. D. Wright, C. K. Angerhofer, J. Org. Chem. 1996, 61, 3259.
         | Crossref | GoogleScholarGoogle Scholar |

[11]  A. D. Wright, G. M. König, C. K. Angerhofer, P. Greenidge, A. Linden, R. Desqueyroux-Faúndez, J. Nat. Prod. 1996, 59, 710.
         | Crossref | GoogleScholarGoogle Scholar | 8759172PubMed |

[12]  A. D. Wright, H. Wang, M. Gurrath, G. M. König, G. Kocak, G. Neumann, P. Loria, M. Foley, L. Tilley, J. Med. Chem. 2001, 44, 873.
         | Crossref | GoogleScholarGoogle Scholar | 11300869PubMed |

[13]  H. Miyaoka, M. Shimomura, H. Kimura, Y. Yamada, H.-S. Kim, Y. Wataya, Tetrahedron 1998, 54, 13467.
         | Crossref | GoogleScholarGoogle Scholar |

[14]  H. Miyaoka, Y. Abe, N. Sekiya, H. Mitome, E. Kawashima, J. Chem. Soc. Chem. Commun. 2012, 48, 901.
         | Crossref | GoogleScholarGoogle Scholar |

[15]  J. S. Simpson, M. J. Garson, J. N. A. Hooper, E. I. Cline, C. K. Angerhofer, Aust. J. Chem. 1997, 50, 1123.
         | Crossref | GoogleScholarGoogle Scholar |

[16]  A. M. White, G. K. Pierens, T. Skinner-Adams, K. T. Andrews, P. V. Bernhardt, E. H. Krenske, E. Mollo, M. J. Garson, J. Nat. Prod. 2015, 78, 1422.
         | Crossref | GoogleScholarGoogle Scholar | 26056748PubMed |

[17]  A. M. White, K. Dao, D. Vrubliauskas, Z. A. Könst, G. K. Pierens, A. Mándi, K. T. Andrews, T. S. Skinner-Adams, M. E. Clarke, P. T. Narbutas, D. C.-M. Sim, K. L. Cheney, T. Kurtán, M. J. Garson, C. D. Vanderwal, J. Org. Chem. 2017, 82, 13313.
         | Crossref | GoogleScholarGoogle Scholar | 29124922PubMed |

[18]  N. Fusetani, H. J. Wolstenholme, S. Matsunaga, H. Hirota, Tetrahedron Lett. 1991, 32, 7291.
         | Crossref | GoogleScholarGoogle Scholar |

[19]  B. J. Burreson, P. J. Scheuer, J. Finer, J. Clardy, J. Am. Chem. Soc. 1975, 97, 4763.
         | Crossref | GoogleScholarGoogle Scholar |

[20]  T. Okino, E. Yoshimura, H. Hirota, N. Fusetani, Tetrahedron 1996, 52, 9447.
         | Crossref | GoogleScholarGoogle Scholar |

[21]  B. Di Blasio, E. Fattorusso, S. Magno, L. Mayol, C. Pedone, C. Santacroce, D. Sica, Tetrahedron 1976, 32, 473.
         | Crossref | GoogleScholarGoogle Scholar |

[22]  E. J. Dumdei, A. E. Flowers, M. J. Garson, C. J. Moore, Comp. Biochem. Physiol. Part A 1997, 118, 1385.
         | Crossref | GoogleScholarGoogle Scholar |

[23]  L. Mayol, V. Piccialli, D. Sica, Tetrahedron 1987, 43, 5381.
         | Crossref | GoogleScholarGoogle Scholar |

[24]  J. C. Braekman, D. Daloze, C. Moussiaux, C. Stoller, F. Deneubourg, Pure Appl. Chem. 1989, 61, 509.
         | Crossref | GoogleScholarGoogle Scholar |

[25]  P. Jumaryatno, B. L. Stapleton, J. N. A. Hooper, D. J. Brecknell, J. T. Blanchfield, M. J. Garson, J. Nat. Prod. 2007, 70, 1725.
         | Crossref | GoogleScholarGoogle Scholar | 17953446PubMed |

[26]  D. C.-M. Sim, I. W. Mudianta, A. M. White, N. W. Martiningish, J. J. M. Loh, K. L. Cheney, M. J. Garson, Fitoterapia 2018, 126, 69.
         | Crossref | GoogleScholarGoogle Scholar |

[27]  F. Cafieri, E. Fattorusso, S. Magno, C. Santacroce, D. Sica, Tetrahedron 1973, 29, 4259.
         | Crossref | GoogleScholarGoogle Scholar |

[28]  S. Jaisamut, S. Prabpai, C. Tancharoen, S. Yuenyongsawad, S. Hannongbua, P. Kongsaeree, A. Plubrukarn, J. Nat. Prod. 2013, 76, 2158.
         | Crossref | GoogleScholarGoogle Scholar | 24200393PubMed |

[29]  F. J. Jäggi, P. Buchs, C. Ganter, Helv. Chim. Acta 1980, 63, 872.
         | Crossref | GoogleScholarGoogle Scholar |

[30]  Schrödinger, Macromodel Release 2018–1 2018 (Schrödinger: New York, NY).

[31]  M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, G. A. Petersson, H. Nakatsuji, X. Li, M. Caricato, A. V. Marenich, J. Bloino, B. G. Janesko, R. Gomperts, B. Mennucci, H. P. Hratchian, J. V. Ortiz, A. F. Izmaylov, J. L. Sonnenberg, D. Williams-Young, F. Ding, F. Lipparini, F. Egidi, J. Goings, B. Peng, A. Petrone, T. Henderson, D. Ranasinghe, V. G. Zakrzewski, J. Gao, N. Rega, G. Zheng, W. Liang, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, K. Throssell, J. A. Montgomery, Jr, J. E. Peralta, F. Ogliaro, M. J. Bearpark, J. J. Heyd, E. N. Brothers, K. N. Kudin, V. N. Staroverov, T. A. Keith, R. Kobayashi, J. Normand, K. Raghavachari, A. P. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, J. M. Millam, M. Klene, C. Adamo, R. Cammi, J. W. Ochterski, R. L. Martin, K. Morokuma, O. Farkas, J. B. Foresman, D. J. Fox, Gaussian 16, Revision B.01 2016 (Gaussian, Inc.: Wallingford, CT).

[32]  A. V. Marenich, C. J. Cramer, D. G. Truhlar, J. Phys. Chem. B 2009, 113, 6378.
         | Crossref | GoogleScholarGoogle Scholar | 19366259PubMed |

[33]  The Boltzmann population was found to be 80:20 when calculated with B3LYP/6-311+G(2d,p) but when calculated with M06-2X/6-311+G(2d,p) was found to be 53 : 47. Calculation of the chemical shifts using the two populations showed that there was very little difference in the MAE.

[34]  P. Karuso, A. Poiner, P. J. Scheuer, J. Org. Chem. 1989, 54, 2095.
         | Crossref | GoogleScholarGoogle Scholar |

[35]  M. J. Garson, J. Chem. Soc. Chem. Commun. 1986, 35.
         | Crossref | GoogleScholarGoogle Scholar |

[36]  C. H. McCulley, D. J. Tantillo, J. Phys. Chem. A 2018, 122, 8058.
         | Crossref | GoogleScholarGoogle Scholar | 30209949PubMed |

[37]  When secondary carbocation 6, initially optimized with B3LYP/6-31+G(d,p), was subjected to geometry reoptimisation with B3LYP-D3/6-31+G(d,p), its carbon skeleton remained intact. In contrast, upon reoptimisation with mPW1PW91/6-31+G(d,p), 6 rearranged to 5. Optimisations of 6 using the CPCM continuum solvent model to simulate the dielectric constant of an enzyme active site (solvent = diethyl ether) with B3LYP/6-31+G(d,p) enabled us to locate two structures for 6, each representing a different isopropyl rotamer. Only one conformer of 6 was located as an energy minimum in the gas phase.

[38]  M. Castiñeira Reis, C. Silva López, O. Nieto Faza, D. J. Tantillo, Chem. Sci. 2019, 10, 2159.
         | Crossref | GoogleScholarGoogle Scholar | 30881640PubMed |

[39]  For example, the product ratio could be influenced by steric constraints within the active site or by the presence of carbocation-stabilising groups at specific locations around the active site.

[40]  N. Fusetani, H. J. Wolstenholme, K. Shinoda, N. Asai, S. Matsunaga, H. Onuki, H. Hirota, Tetrahedron Lett. 1992, 33, 6823.
         | Crossref | GoogleScholarGoogle Scholar |

[41]  K. E. Kassühlke, B. C. M. Potts, D. J. Faulkner, J. Org. Chem. 1991, 56, 3747.
         | Crossref | GoogleScholarGoogle Scholar |

[42]  H. Ishiyama, A. Hashimoto, J. Fromont, Y. Hoshino, Y. Mikami, J. Kobayashi, Tetrahedron 2005, 61, 1101.
         | Crossref | GoogleScholarGoogle Scholar |

[43]  A. T. Pham, T. Ichiba, W. Yoshida, P. J. Scheuer, T. Uchida, J. Tanaka, T. Higa, Tetrahedron Lett. 1991, 32, 4843.
         | Crossref | GoogleScholarGoogle Scholar |

[44]  M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery, Jr, J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, O. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian 09, Revision A.02 2009 (Gaussian, Inc.: Wallingford, CT).

[45]  C. Lee, W. Yang, R. G. Parr, Phys. Rev. B Condens. Matter 1988, 37, 785.
         | Crossref | GoogleScholarGoogle Scholar | 9944570PubMed |

[46]  A. D. Becke, J. Chem. Phys. 1993, 98, 1372.
         | Crossref | GoogleScholarGoogle Scholar |

[47]  A. D. Becke, J. Chem. Phys. 1993, 98, 5648.
         | Crossref | GoogleScholarGoogle Scholar |

[48]  P. J. Stephens, F. J. Devlin, C. F. Chabalowski, M. J. Frisch, J. Phys. Chem. 1994, 98, 11623.
         | Crossref | GoogleScholarGoogle Scholar |

[49]  K. Burke, J. P. Perdew, Y. Wang, in Electronic Density Functional Theory: Recent Progress and New Directions (Eds J. F. Dobson, G. Vignale, M. P. Das) 1998, pp. 81–111 (Plenum: New York, NY).

[50]  J. P. Perdew, in Electronic Structure of Solids ‘91 (Eds P. Ziesche, H. Eschrig) 1991, pp. 11–20 (Akademie: Berlin).

[51]  J. P. Perdew, J. A. Chevary, S. H. Vosko, K. A. Jackson, M. R. Pederson, D. J. Singh, C. Fiolhais, Phys. Rev. B Condens. Matter 1992, 46, 6671.
         | Crossref | GoogleScholarGoogle Scholar | 10002368PubMed |

[52]  J. P. Perdew, K. Burke, Y. Wang, Phys. Rev. B Condens. Matter 1996, 54, 16533.
         | Crossref | GoogleScholarGoogle Scholar | 9985776PubMed |

[53]  C. Adamo, V. Barone, J. Chem. Phys. 1998, 108, 664.
         | Crossref | GoogleScholarGoogle Scholar |

[54]  C. Gonzalez, H. B. Schlegel, J. Chem. Phys. 1989, 90, 2154.
         | Crossref | GoogleScholarGoogle Scholar |

[55]  C. Gonzalez, H. B. Schlegel, J. Phys. Chem. 1990, 94, 5523.
         | Crossref | GoogleScholarGoogle Scholar |

[56]  C. Y. Legault, CYLview 1.0b 2009 (Université de Sherbrooke: Sherbrooke, Canada). Available at: http://www.cylview.org

[57]  M. J. Chua, D. Robaa, T. S. Skinner-Adams, W. Sippl, K. T. Andrews, Int. J. Parasitol. 2018, 8, 189.
         | Crossref | GoogleScholarGoogle Scholar |

[58]  W. Huber, J. C. Koella, Acta Trop. 1993, 55, 257.
         | Crossref | GoogleScholarGoogle Scholar | 8147282PubMed |