Australian Journal of Chemistry Australian Journal of Chemistry Society
An international journal for chemical science

Ilimaquinone and 5-epi-Ilimaquinone: Beyond a Simple Diastereomeric Ratio, Biosynthetic Considerations from NMR-Based Analysis

Asmaa Boufridi A , David Lachkar A , Dirk Erpenbeck B , Mehdi A. Beniddir A , Laurent Evanno A , Sylvain Petek C D , Cécile Debitus C E and Erwan Poupon A E
+ Author Affiliations
- Author Affiliations

A BioCIS, Université Paris-Sud, Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay, Châtenay-Malabry 92290, France.

B Department of Earth and Environmental Sciences and GeoBio-Center LMU, Ludwig-Maximilians-Universität Munich, Richard-Wagner-Str. 10, Munich 80333, Germany.

C Institut de Recherche pour le Développement (IRD), Ecosystèmes Insulaires Océaniens (UMR EIO), BP529, Papeete 98713, Polynésie-Française, France.

D Current address: Laboratoire des sciences de l'environnement marin (LEMAR), Institut Universitaire Européen de la Mer (IUEM), Technopôle Brest-Iroise, Rue Dumont d'Urville, Plouzané 29280, France.

E Corresponding authors. Email:;

Australian Journal of Chemistry 70(6) 743-750
Submitted: 2 August 2016  Accepted: 17 November 2016   Published: 20 December 2016


Dactylospongia metachromia and Dactylospongia elegans collected from French Polynesia were studied with a particular focus on the variation of the diastereomeric ratio between ilimaquinone (4) and 5-epi-ilimaquinone (5). More than 100 samples, covering an area of 4100 km2, were studied to try to clarify this intriguing issue. Nuclear magnetic resonance appeared as the non-destructive, straightforward technique of choice for a relative quantitative study. A random distribution, unique at that point in nature, is observed and leads to biosynthetic considerations. Biological evaluation of both compounds was also performed and showed moderate discrepancies in cytotoxicity and apoptosis induction.


[1]  See p. 899 in: J.-M. Kornprobst, Encyclopedia of Marine Natural Products 2014 (Wiley-Blackwell: Weinheim).

[2]  (a) Selected review articles: M. Gordaliza, Mar. Drugs 2012, 10, 358.
         | CrossRef | 1:CAS:528:DC%2BC38XivVKiurs%3D&md5=e502804f18063bd26419a9e5e0656014CAS | open url image1
      (b) M. Gordaliza, Mar. Drugs 2010, 8, 2849.
         | CrossRef | open url image1
         (c) R. J. Capon, in Studies in Natural Products Chemistry: Structure and Chemistry (Part C) (Ed. Atta-ur Rahman) 1995, Vol. 15, pp. 289–326 (Elsevier: Amsterdam).

[3]  (a) For selected examples on antitumoral activities, see: H.-Y. Lee, K. J. Chung, I. H. Hwang, J. Gwak, S. Park, B. G. Ju, E. Yun, D.-E. Kim, Y.-H. Chung, M. Na, G.-Y. Song, S. Oh, Mar. Drugs 2015, 13, 543.
         | CrossRef | open url image1
      (b) S. Park, E. Yun, I. H. Hwang, S. Yoon, D.-E. Kim, J. S. Kim, M. Na, G.-Y. Song, S. Oh, Mar. Drugs 2014, 12, 3231.
         | CrossRef | open url image1
      (c) M. T. Do, M. Na, H. G. Kim, T. Khanal, J. H. Choi, S. W. Jin, S. H. Oh, I. H. Hwang, Y. C. Chung, H. S. Kim, T. C. Jeong, H. G. Jeong, Food Chem. Toxicol. 2014, 71, 51.and references cited therein.
         | CrossRef | open url image1
      (d) For antiviral activities, see: S. Loya, A. Hizi, J. Biol. Chem. 1993, 268, 9323. open url image1
      (e) S. Loya, R. Tal, Y. Kashman, A. Hizi, Antimicrob. Agents Chemother. 1990, 34, 2009.
         | CrossRef | open url image1

[4]  (a) Ilimaquinone (4) was first isolated from Hippiospongia metachromia (see ref. [9] for taxonomy details). See: R. T. Luibrand, T. R. Erdman, J. J. Vollmer, P. J. Scheuer, J. Finer, J. Clardy, Tetrahedron 1979, 35, 609.
         | CrossRef | 1:CAS:528:DyaE1MXlslGmsbk%3D&md5=9c2a15dafbaf54eb199837461c4cbaa1CAS | open url image1
      (b) The absolute configuration was later revised, see: R. J. Capon, J. K. MacLeod, J. Org. Chem. 1987, 52, 5059.
         | CrossRef | open url image1

[5]  5-epi-Ilimaquinone (5) was first isolated from a Fenestraspongia sp. specimen (which was ‘in an unusually poor condition for identification’); see also ref. [4b] for stereochemical revision: B. Carté, C. B. Rose, D. J. Faulkner, J. Org. Chem. 1985, 50, 2785.
         | CrossRef | open url image1

[6]  5,8-epi-Ilimaquinone (6) was recently isolated from D. elegans from the coast of Palau, see: L. Du, Y.-D. Zhou, D. G. Nagle, J. Nat. Prod. 2013, 76, 1175.
         | CrossRef | 1:CAS:528:DC%2BC3sXoslSquro%3D&md5=f7aeafd1a4318abb2a14d0abe2bf597cCAS | open url image1

[7]  (a) Isospongiaquinone (7) was isolated from a sponge ‘tentatively classified as Stelospongia conulata’; no stereochemistry was provided at that time, see: R. Kazlauskas, P. T. Murphy, R. G. Warren, R. J. Wells, J. F. Blount, Aust. J. Chem. 1978, 31, 2685.
         | CrossRef | 1:CAS:528:DyaE1MXhtlGgsLY%3D&md5=b4240dd171c07ff407b45c031fb9573dCAS | open url image1
      (b) The absolute stereochemistry of 7 was later determined by chemical correlations, see: R. J. Capon, J. Nat. Prod. 1990, 53, 753.
         | CrossRef | open url image1

[8]  (a) P. A. Takizawa, J. K. Yucel, B. Veit, D. J. Faulkner, T. Deerinck, G. Soto, M. Ellisman, V. Malhotra, Cell 1993, 73, 1079.
         | CrossRef | 1:CAS:528:DyaK3sXks1ejs74%3D&md5=25650efb2dcc11eef46c7c3ac767c201CAS | open url image1
      (b) B. Veit, J. K. Yucel, V. Malhotra, J. Cell Biol. 1993, 122, 1197.
         | CrossRef | open url image1

[9]  Dactylospongia metachromia de Laubenfels 1954 (Thorectidae), also formerly named Hippospongia metachromia de Laubenfels 1954 (Spongidae), see: R. van Soest, in World Porifera Database (Eds R. W. M. Van Soest, N. Boury-Esnault, J. N. A Hooper, K. Rützler, N. J. de Voogd, B. Alvarez de Glasby, E. Hajdu, A. B. Pisera, R. Manconi, C. Schoenberg, D. Janussen, K. R. Tabachnick, M. Klautau, B. Picton, M. Kelly, J. Vacelet, M. Dohrmann, M.-C. Díaz, P. Cárdenas) 2015. Available at and (accessed 25 June 2015).

[10]  Dactylospongia elegans Thiele 1899 (Thorectidae), also formerly named Luffarella elegans Thiele 1899 (Thorectidae), see: R. van Soest, in World Porifera Database (Eds R. W. M. Van Soest, N. Boury-Esnault, J. N. A. Hooper, K. Rützler, N. J. de Voogd, B. Alvarez de Glasby, E. Hajdu, A. B. Pisera, R. Manconi, C. Schoenberg, D. Janussen, K. R. Tabachnick, M. Klautau, B. Picton, M. Kelly, J. Vacelet, M. Dohrmann, M.-C. Díaz, P. Cárdenas) 2015. Available at (accessed 25 June 2015).

[11]  Cyanobacterial symbionts were shown to produce chlorinated metabolites, whereas sesquiterpenoids were found only in the sponge cells, see: M. D. Unson, D. J. Faulkner, Experientia 1993, 49, 349.
         | CrossRef | 1:CAS:528:DyaK3sXltlGitbk%3D&md5=1bcaac09000927a9398ce260e27646ceCAS | open url image1

[12]  (a) Avarol (dihydro-1) and congeners were found within sponge choanocytes, see: M.-J. Uriz, X. Turon, J. Galera, J. M. Tur, Cell Tissue Res. 1996, 285, 519.
         | CrossRef | open url image1
      (b) Avarol was produced from cultures of primmorphs from Dysidea avara, see: W. E. G. Müller, M. Böhm, R. Batel, S. De Rosa, G. Tommonaro, I. M. Müller, H. C. Schröder, J. Nat. Prod. 2000, 63, 1077.
         | CrossRef | open url image1
      (c) Very interestingly, the variation of concentrations of avarol depending on time period and biotope-dependent factors was evaluated, see: S. De Caralt, D. Bry, N. Bontemps, X. Turon, M.-J. Uriz, B. Banaigs, Mar. Drugs 2013, 11, 489.
         | CrossRef | open url image1

[13]  (a) The gathering and cross-checking of data from literature dealing with ilimaquinones shows a variation of 4/5 ratio between publications but strangely this statement is never discussed as such based on multi-sample studies. Reports of co-isolation of 4 and 5 include D. elegans from Okinawa, Japan and 4/5 (96/4) ratio based on amounts presented in the experimental section after purification and not a ratio based on crude extract analysis, see: H. Mitome, T. Nagasawa, H. Miyaoka, Y. Yamada, R. W. M. van Soest, J. Nat. Prod. 2001, 64, 1506.
         | CrossRef | 1:CAS:528:DC%2BD3MXotFykur0%3D&md5=fcfac5bb96f956d12e2b3bd782dbd16bCAS | open url image1
      (b) Dactylospongia elegans from West Flores, Indonesia: 4/5 (3/5 ratio based on amounts presented in experimental section and not a ratio based on crude extract analysis), see: S. Aoki, D. Kong, K. Matsui, R. Rachmat, M. Kobayashi, Chem. Pharm. Bull. 2004, 52, 935.
         | CrossRef | open url image1
      (c) Dactylospongia elegans from Truant Island, Australia: 4/5 (1/1 mixture, not separated), see: S. P. B. Ovenden, J. L. Nielson, C. H. Liptrot, R. H. Willis, D. M. Tapiolas, A. D. Wright, C. A. Motti, J. Nat. Prod. 2011, 74, 65.
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      (d) Dactylospongia elegans from Fiji: only the presence of 5 is reported, see: J. Rodríguez, E. Quiñoa, R. Riguera, B. M. Peters, L. M. Abrell, P. Crews, Tetrahedron 1992, 48, 6667.
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         (e) Fenestraspongia sp., Thorectidae from Urukthapel Island, Palau: 4/5 (6/4 mixture), see ref. [5].
      (f) Polyfibrospongia australis, Thorectidae (now Fasciospongia turgida, Thorectidae) from Taiwan: mixture of 4 and 5 (no further precision). See: Y.-C. Shen, P.-W. Hsieh, J. Nat. Prod. 1997, 60, 93.
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[14]  Having the same decalin ring system but with, apparently, opposite absolute configuration, asmarines AF (isolated from a specimen of Raspailia sp.) bear diazepino-purines a in place of the quinone. They also exists as pairs of epimers at C-5 (asmarines A-B, C-D, E-F respectively), see: T. Yosief, A. Rudi, Y. Kashman, J. Nat. Prod. 2000, 63, 299. In the latter paper, the term ‘epi’ is misleading and refers to a C-5 configuration (S), (R), (S) for asmarines B, D, F, respectively. No indication of the different ratios is given.

[15]  The case of 5,8-di-epi-ilimaquinone (6) described recently by Nagle and coworkers is striking in terms of plausible biosynthetic pathway but is not discussed by the authors (see ref. [6]). It would apparently necessitate an unusual precursor i.e. Z,E-(8).

[16]  (a) The lack of selectivity of terpene cyclases in terms of end products is now well documented. See for example: M. Köksal, Y. Jin, R. M. Coates, R. Croteau, D. W. Christianson, Nature 2011, 469, 116.
         | CrossRef | open url image1
      (b) See also, among others: V. Gonzalez, S. Touchet, D. J. Grundy, J. A. Faraldos, R. K. Allemann, J. Am. Chem. Soc. 2014, 136, 14505.
         | CrossRef | open url image1

[17]  K. W. L. Yong, A. Jankam, J. N. A. Hooper, A. Suksamrarn, M. J. Garson, Tetrahedron 2008, 64, 6341.
         | CrossRef | 1:CAS:528:DC%2BD1cXms1ylsL0%3D&md5=88773f927da2e78ca2211691afce5524CAS | open url image1

[18]     (a) Neomamanuthaquinone 15 was isolated from a Dactylospongia sp. as a natural substance (see ref. [17]) but was described before as an semi-synthetic compound. See: (a) ref. [5],
      (b) J. C. Swersey, L. R. Barrows, C. M. Ireland, Tetrahedron Lett. 1991, 32, 6687.
         | CrossRef | open url image1
      (c) N. K. Utkina, V. A. Denisenko, O. V. Scholokova, A. E. Makarchenko, J. Nat. Prod. 2003, 66, 1263.
         | CrossRef | open url image1

[19]  S. Urban, R. J. Capon, J. Nat. Prod. 1992, 55, 1638.
         | CrossRef | 1:CAS:528:DyaK3sXls1WmtQ%3D%3D&md5=352b43241e02f89b3c088da8bb706a96CAS | open url image1

[20]  C. Payri, French Oceanographic Cruises – BSM-FIDJI 2007. Available at: 10.17600/7100030

[21]  C. Debitus, French Oceanographic Cruises – BSMPF-1 2009. Available at: 10.17600/9100030

[22]  C. Debitus, French Oceanographic Cruises – TUAM’2011 2011. Available at: 10.17600/11100010

[23]  E. Sambrook, F. Fritsch, T. Maniatis, Molecular Cloning 1989 (Cold Spring Harbor Press: New York, NY).

[24]  G. Wörheide, Facies 1998, 38, 1.
         | CrossRef | open url image1

[25]  C. Chombard, N. Boury-Esnault, S. Tillier, Syst. Biol. 1998, 47, 351.
         | CrossRef | 1:STN:280:DC%2BD38zitlentg%3D%3D&md5=d81b5386d8f3fb7ffb59fcf813315d96CAS | open url image1

[26]  W. P. Maddison, D. R. Maddison, MacClade 3: Analysis of Phylogeny and Character Evolution 1992 (Sinauer Associates: Sunderland, MA).

[27]  M. Kearse, R. Moir, A. Wilson, S. Stones-Havas, M. Cheung, S. Sturrock, S. Buxton, A. Cooper, S. Markowitz, C. Duran, T. Thierer, B. Ashton, P. Meintjes, A. Drummond, Bioinformatics 2012, 28, 1647.
         | CrossRef | open url image1

[28]  J. Pöppe, P. Sutcliffe, J. N. A. Hooper, G. Wörheide, D. Erpenbeck, PLoS One 2010, 5, e9950.
         | CrossRef | open url image1

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