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Structure–activity relationship of ochratoxin A and synthesized derivatives: importance of amino acid and halogen moiety for cytotoxicity

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Abstract

The enigma why the mycotoxin ochratoxin A (OTA) impairs cell and organ function is still not solved. However, an interaction with target molecules is a prerequisite for any observed adverse effect. This interaction depends on characteristics of the target molecule as well as on the OTA molecule itself. OTA has different structural moieties which may be relevant for these interrelations including a halogen (chlorine) and an amino acid group (phenylalanine). To test their importance for the impact of OTA, detailed structure–activity studies with various OTA derivatives were performed. For this, 23 OTA derivatives were available, which were modified by either an exchange of the halogen moiety against another halogen (fluorine, iodine or bromine) or by the amino acid moiety against another one (tyrosine or alanine) or a combination of both. Additionally, the configuration of the 3R carbon atom was changed to 3S. These derivatives were tested in human renal cells for their ability to induce cell death (cytotoxicity, apoptosis, necrosis), their impact on collagen protein secretion and for their influence on gene expression. It turned out that the substitution of the amino acid moiety against tyrosine or alanine almost completely prevented the adverse effects of OTA. The exchange of the halogen moiety had minor effects and the inversion of the stereochemistry at C3 did not prevent the effects of OTA. Therefore, we conclude that the amino acid moiety of OTA is indispensable for the interaction of OTA with its target molecules.

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Acknowledgments

We thank Jenny Friedrich for her help in RT-PCR. We thank Kenichiro Itami and Shigehiro Yamaguchi (both from Nagoya University) for their support with the synthesis of the OTA derivatives within the International Research Training Group Münster-Nagoya. This work was supported by the Deutsche Forschungsgemeinschaft (DFG, HU 730/12-1 and SCHW 1515/2-1).

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Authors and Affiliations

  1. Institute of Food Chemistry, Westfälische Wilhelms-Universität Münster, Corrensstraße 45, 48149, Münster, Germany

    Ulrike Rottkord, Christopher Röhl, Ines Ferse & Hans-Ulrich Humpf

  2. Julius-Bernstein-Institute of Physiology, Martin-Luther-Universität Halle-Wittenberg, Halle (Saale), Germany

    Marie-Christin Schulz, Uwe Rückschloss, Michael Gekle & Gerald Schwerdt

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  1. Ulrike Rottkord
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  2. Christopher Röhl
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  3. Ines Ferse
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  4. Marie-Christin Schulz
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  5. Uwe Rückschloss
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  6. Michael Gekle
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  8. Hans-Ulrich Humpf
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Correspondence to Gerald Schwerdt or Hans-Ulrich Humpf.

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Rottkord, U., Röhl, C., Ferse, I. et al. Structure–activity relationship of ochratoxin A and synthesized derivatives: importance of amino acid and halogen moiety for cytotoxicity. Arch Toxicol 91, 1461–1471 (2017). https://doi.org/10.1007/s00204-016-1799-3

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