In Vitro Effects of Fungal Phytotoxins on Cancer Cell Viability: First Insight into Structure Activity Relationship of a Potent Metabolite of Cochliobolus australiensis Radicinin

Abstract

Natural compounds have always represented an important source for new drugs. Although fungi represent one such viable source, to date, no fungal metabolite has been marketed as an anticancer drug. Based on our work with phytotoxins as potential chemical scaffolds and our recent findings involving three phytopathogenic fungi, i.e., Cochliobolus australiensis, Kalmusia variispora and Hymenoscyphus fraxineus, herein, we evaluate the in vitro anti-cancer activity of the metabolites of these fungi by MTT assays on three cancer cell models harboring various resistance levels to chemotherapeutic drugs. Radicinin, a phytotoxic dihydropyranopyran-4,5-dione produced by Cochliobolus australiensis, with great potential for the biocontrol of the invasive weed buffelgrass (Cenchrus ciliaris), showed significant anticancer activity in the micromolar range. Furthermore, a SAR study was carried out using radicinin, some natural analogues and hemisynthetic derivatives prepared by synthetic methods developed as part of work aimed at the potential application of these molecules as bioherbicides. This investigation opens new avenues for the design and synthesis of novel radicinin analogues as potential anticancer agents.

Keywords: Cochliobolus australiensis; SAR study; anticancer; fungi; natural and hemisynthetic derivatives; phytotoxins; radicinin.

Figure 1

Structures of the fungal metabolites radicinin, chloromonilinic acid B, chloromonilinic acid D (1–3), viridiol, 1-deoxyviridiol, hyfraxinic acid (4–6), massarilactone D and H (7,8) that were produced by Cochliobolus australiensis, Hymenoscyphus fraxineus and Kalmusia variispora.

Figure 2

Structure of radicinol (9), 3-epi-radicinol (10), 3-O-acetyl radicinin (11), 3-O-mesyl radicinin (12), 3-O-(5-azidopentanoyl radicinin (13), 3,4-O,O’-diacetylradicinol (14), (±)-3-deoxyradicinin (15), 2,3-dehydroradicinin (16), 4-methoxy-6-methyl-2H-pyran-2-one (17), 3-bromo-4-methoxy-6-methyl-2H-pyran-2-one (18), (E)-4-methoxy-6-(propen-1-yl)-2H-pyran-2-one (19), and (E)-3-bromo-4-methoxy-6-(propen-1-yl)-2H-pyran-2-one (20), synthetic intermediates of (±)-3-deoxyradicinin (15).