Antimicrobial, Antiproliferative, Cytotoxic, and Tau Inhibitory Activity of Rubellins and Caeruleoramularin Produced by the Phytopathogenic Fungus Ramularia collo-cygni

Abstract

Photodynamically active anthraquinone derivatives produced by the phytopathogenic fungus Ramularia collo-cygni are known to cause a barley leaf-spot disease, but data about light-dependent and independent bioactivity have been sparse to date. We therefore conducted for the first time a broad bioactivity profiling of rubellins B, C, D, and E and caeruleoramularin. Antibacterial but not antiviral activity is reported with light-dependent increase. Furthermore, when tested without illumination, compounds exerted antiproliferative and cytotoxic activity in a series of human tumor cell lines. Inhibition of tau protein assembly was observed as well.

Key words

Ramularia collo‐cygni - Hyphomycetes - anthraquinones - rubellins - antimicrobial activity - antiproliferative activity - cytotoxicity

References

• 1 Miethbauer S, Haase S, Schmidtke K –U, Günther W, Heiser I, Liebermann B. Biosynthesis of photodynamically active rubellins and structure elucidation of new anthraquinone derivatives produced by Ramularia collo-cygni.  Phytochemistry. 2006;  67 1206-1213
• 2 Miethbauer S, Günther W, Schmidtke K –U, Heiser I, Gräfe S, Gitter B, Liebermann B. Uredinorubellins and caeruleoramularin, novel anthraquinone derivatives produced by two species of the genus Ramularia.  J Nat Prod. 2008;  71 1371-1375
• 3 Miethbauer S, Heiser I, Liebermann B. The phytopathogenic fungus Ramularia collo-cygni produces biologically active rubellins on infected barley leaves.  J Phytopathol. 2003;  151 665-668
• 4 Heiser I, Sachs E, Liebermann B. Photodynamic oxygen activation by rubellin D, a phytotoxin produced by Ramularia collo-cygni (Sutton et Waller).  Physiol Mol Plant Pathol. 2003;  62 29-36
• 5 Heiser I, Hess M, Schmidtke K-U, Vogler U, Miethbauer S, Liebermann B. Fatty acid peroxidation by rubellin B, C and D, phytotoxins produced by Ramularia collo-cygni (Sutton et Waller).  Physiol Mol Plant Pathol. 2004;  64 135-143
• 6 Lown J W. Anthracycline and anthraquinone anticancer agents – current status and recent developments.  Pharmacol Ther. 1993;  60 185-214
• 7 Ali A M, Ismail N H, Mackeen M M, Yazan L S, Mohamed S M, Ho A SH, Lajis N H. Antiviral, cyototoxic and antimicrobial activities of anthraquinones isolated from the roots of Morinda elliptica.  Pharmaceut Biol. 2000;  38 298-301
• 8 Chen R F, Shen Y C, Huang H S, Liao J F, Ho L K, Chou Y C, Wang W Y, Chen C F. Evaluation of the anti-inflammatory and cytotoxic effects of anthraquinones and anthracenes derivatives in human leucocytes.  J Pharm Pharmacol. 2004;  56 915-919
• 9 Huang Q, Lu G, Sben H M, Cbung M CM, Ong C N. Anti-cancer properties of anthraquinones from rhubarb.  Med Res Rev. 2007;  27 609-630
• 10 Schmidtke M, Schnittler U, Jahn B, Dahse H-M, Stelzner A. A rapid assay for evaluation of antiviral activity against Coxsackie virus B3, influenza virus A, and herpes simplex virus type 1.  J Virol Methods. 2001;  95 133-143
• 11 Semple S J, Pyke S M, Reynolds G D, Flower R L. In vitro antiviral activity of the anthraquinone chrysophanic acid against poliovirus.  Antiviral Res. 2001;  49 169-178
• 12 Gareis M. Diagnostischer Zellkulturtest (MTT-Test) für den Nachweis von zytotoxischen Kontaminanten und Rückständen.  J Verbr Lebensm. 2006;  1 354-363
• 13 Matsuda H, Shimoda H, Morikawa T, Yoshikawa M. Phytoestrogens from the roots of Polygonum cuspidatum (Polygonaceae): structure-requirement of hydroxyanthraquinones for estrogenic activity.  Bioorg Med Chem Lett. 2001;  11 1839-1842
• 14 Pickhardt M, Gazova Z, von Bergen M, Khlistunova I, Wang Y, Hascher A, Mandelkow E M, Biernat J, Mandelkow E. Anthraquinones inhibit tau aggregation and dissolve Alzheimer's paired helical filaments in vitro and in cells.  J Biol Chem. 2005;  280 3628-3635
• 15 Afonin S, Glaser R W, Berditchevskaja M, Wadhwani P, Gührs K-H, Möllmann U, Perner A, Ulrich A S. 4‐Fluoro-phenylglycine as a label for 19F‐NMR structure analysis of membrane associated peptides.  Chembiochem. 2003;  4 1151-1163
• 16 Heinisch L, Wittmann S, Stoiber T, Berg A, Ankel-Fuchs D, Möllmann U. Highly antibacterial active aminoacylpenicillin conjugates with bis-catecholate siderophores based on secondary diamino acids and related compounds.  J Med Chem. 2002;  45 3032-3040
• 17 Nain M, Hinder F, Gong J H, Schmidt A, Bender A, Sprenger H, Gemsa D. Tumor necrosis factor-alpha production of influenza A virus-infected macrophages and potentiating effect of lipopolysaccharides.  J Immunol. 1990;  145 1921-1928
• 18 Dahse H –M, Schlegel B, Gräfe U. Differentiation between inducers of apoptosis and nonspecific cytotoxic drugs by means of cell analyzer and immunoassay.  Pharmazie. 2001;  56 489-491
• 19 Gaube F, Wölfl S, Pusch L, Kroll T C, Hamburger M. Gene expression profiling reveals effects of Cimicifuga racemosa (L.) Nutt. (black cohosh) on the estrogen receptor positive human breast cancer cell line MCF‐7.  BMC Pharmacol. 2007;  7 11
• 20 Pickhardt M, Larbig G, Khlistunova I, Coksezen A, Meyer B, Mandelkow E M, Schmidt B, Mandelkow E. Phenylthiazolyl-hydrazide and its derivatives are potent inhibitors of tau aggregation and toxicity in vitro and in cells.  Biochemistry. 2007;  46 10016-10023