Ophobiolin A - a toxic fungal sesterterpenoid toxin. – University of Copenhagen

NaToxAq > Toxin of the week > Ophobiolin A

15 October 2018

Ophobiolin A - a toxic fungal sesterterpenoid toxin.

Natural toxin

Is it a threat for humans or not? It is important to highlight that not all the natural toxins can be a threat for humans, and a lot of these can be used as a powerful inhibitory compound to fight certain pathologies.

Figure 1: Ophiobolin A chemical structure.
Click image for 3D structure

A group of terpenes recognized as phytotoxins are the ophiobolins, their structure is characterized by a specific tri- or tetracyclic ring system (Figure 1). More than 30 of these secondary metabolites have been described to date and assigned into several subgroups [1]. Ophiobolin A (OPA) is a sesterterpene-type (C25) compounds produced by fungal species belonging to the genera Bipolaris, Cochliobolus, Drechslera, Cephalosporium and Aspergillus. His high-resolution mass spectra shows a peak at 401.2686 [M+H]+ and an adductat 423.2506 [M+Na]+. Other fragments at 383, 365 and 347 m/z can be recognised for the loss of one to three water molecules respectively by the [M+H]+ ion (Figure 2).

Figure 2:HPLC-UV chromatogram of the purified OPA at
230 nm (A); and the acquired mass spectra by ESI-MS in
positive (B) and in negative mode (C); as well as by
ESI-MS/MS after the fragmentation of m/z 401.4
in positive mode (D). [4].
(Click the figure to see a larger image)

It is important to highlight that not all the natural toxins can be a threat for humans, and a lot of these can be used as a powerful inhibitory compound to fight certain pathologies. These compounds show a broad spectrum of biological activities, such as antimicrobial, nematocidic, cytotoxic or HIV-1 integrase inhibitory effects [2]. Natural products are an important source for the development of pharmaceutical drugs, especially in oncology, half of all anticancer drugs developed since the 1940s are natural products or derivatives of natural products [3]. An example of such natural products is ophiobolin A (OPA), which displays cytotoxicity at nanomolar concentrations against a range of cancer cell lines [2]. Even if several studies have been carried out to determine the toxicity of the OPA [4], other studies have shown his potential as inhibitory compound against somatic cancer cell lines. [5].

During a study targeted in ovarian cancer cell line [6], human umbilical vein endothelial cells, nonsmall cell lung cancer [7] and melanoma [8] different effects have been reported.

OPA has been studied altogether with other 25 compounds isolated from phytopathogenic fungi and evaluated their cytotoxicity against cancer cells, providing the initial structure–activity relationship (SAR) data. These data identify the C5, C21-dicarbonyl functionality as critical for anticancer activity in this family of natural products. Dasari et al., 2015 reported the effect of a synthetic OPA with an in vitro evaluation of growth inhibition of lung cancer cells showing that derivatives with the eliminated C5, C21-dicarbonyl functionality, such as pyrrole, imine and cyclic pyrroles compounds without this moiety, have a significantly reduced anticancer activity [5].

On the other hand, several adverse effects have been reported by different authors. Zeng et al., observed a reduction of the sperm motility after treatment with OPA [9]. Furthermore, it has been reported that OPA can induce paraptosis-like cell death trough alterations in the membrane permeability such as increasing in the intracellular Ca2+[8], and potassium [10]. Based on these premises, a Bencsik et al., [4] have published the toxicity effects of OPA on the sperm motility of rats and also humans. In this work, OPA inhibited the motility at a very low concentration, dissipated the mitochondrial membrane potential at mid-level concentration and depleted plasma membrane integrity at moderately higher concentration.

The damaging of sperm mitochondria can be seen in Figure 3 thank of the dissipation of transmembrane potential in the mitochondrial inner membrane, while the plasma membrane permeability barrier remained intact.

In conclusion is interesting to highlight the potentiality of these compounds, against certain pathologies. In particular, ophiobolin A is a promising candidate for the treatment of a type of brain tumor called glioblastomas, which are notoriously difficult to treat with existing medications. [11]. on the other hand, it is important to continue the study on their adverse effects on the human body while molecular identification of these compounds and characterization of their biological activities are the most important goals of studies working on the interface of chemistry and biology research.

Molecular Formula: C25H36O4
Molecular Weight: 400.559 g/mol
CANONICAL SMILES: C[C@H]1C[C@@H](O[C@@]12CC[C@]3([C@H]2C/C=C(\[C@@H]4[C@H](C3)[C@](CC4=O)(C)O)/C=O)C)C
=C(C)C

References:

  1. Wang, Q.X.; Yang, J.L.; Qi, Q.Y.; Bao, L.; Yang, X.L.; Liu, M.M.; Huang, P.; Zhang, L.X.; Chen, J.L.; Cai, L.; Liu,
    H.W. Bioorg. Med. Chem. Lett. 2013, 23, 3547–3550]
  2. Au TK, Chick WS, Leung PC, Life Sci. 2000 Jul 7; 67(7):733-42.
  3. Newman DJ Cragg GM, J. Nat. Prod. 2012 Feb 8, 75(3):311–335.
  4. Bencsik, O.; Papp, T.; Berta, M.; Zana, A.; Forgó, P.; Dombi, G.; Andersson, M.A.; Salkinoja-Salonen, M.; Vágvölgyi,
    C.; Szekeres, A. Toxins (Basel). 2014 Sep; 6(9): 2857–2871
  5. Dasari R. Masi M. Lisy R. Ferdérin M. Bioorganic Med. Chem. Lett. 2015 Oct. 15; 25(20): 4544-4548
  6. de Vries-van Leeuwen IJ, Kortekaas-Thijssen C, Nzigou Mandouckou JA, Kas S, Evidente A and de Boer AH:
    Fusicoccin- Cancer Lett 2010. 293:198–206
  7. Shen L, Kondo Y, Ahmed S, Boumber Y, Konishi K, Guo Y, Chen X, Vilaythong JN and Issa JP: Cancer Res 2007.
    67:11335–11343
  8. Bury M, Novo-Uzal E, Andolfi A, Cimini S, Wauthoz N, Heffeter P, Lallemand B, Avolio F, Delporte C, Cimmino A,
    Int J Oncol 2013;43:575–585.
  9. Zeng HT, Tulsiani DR J Cell Sci. 2003 May 15; 116(Pt 10):1981-9
  10. Cocucci S.M., Morgutti S., Cocucci M., Gianani L. Plant Sci. Lett. 1983;32:9–16
  11. eLife 2016;5:e14601 DOI: 10.7554/eLife.14601