In vitro anticancer activity, toxicity and structure-activity relationships of phyllostictine A, a natural oxazatricycloalkenone produced by the fungus Phyllosticta cirsii
- Laboratoire de Toxicologie, Faculte de Pharmacie de Pharmacie, Universite Libre de Bruxelles (ULB), Brussels (Belgium)
- Laboratoire de Chimie Analytique, Toxicologie et de Chimie Physique Appliquee, Faculte de Pharmacie de Pharmacie, Universite Libre de Bruxelles (ULB), Brussels (Belgium)
- Dipartimento di Scienze, del Suolo, della Pianta, dell'Ambiente e delle Produzioni Animali, Universita di Napoli Federico II, Portici (Italy)
- INSERM U-837, Jean-Pierre Aubert Research Center (JPARC), Team Molecular and Cellular Targeting for Cancer Treatment, Institut pour la Recherche sur le Cancer de Lille, Lille (France)
- Istituto di Scienze delle Produzioni Alimentari, CNR, Bari (Italy)
- Cell and Tissue Laboratory, URPHYM, University of Namur (FUNDP), Namur (Belgium)
- Laboratoire de Chimie Pharmaceutique Organique, Faculte de Pharmacie de Pharmacie, Universite Libre de Bruxelles (ULB), Brussels (Belgium)
The in vitro anticancer activity and toxicity of phyllostictine A, a novel oxazatricycloalkenone recently isolated from a plant-pathogenic fungus (Phyllosticta cirsii) was characterized in six normal and five cancer cell lines. Phyllostictine A displays in vitro growth-inhibitory activity both in normal and cancer cells without actual bioselectivity, while proliferating cells appear significantly more sensitive to phyllostictine A than non-proliferating ones. The main mechanism of action by which phyllostictine displays cytotoxic effects in cancer cells does not seem to relate to a direct activation of apoptosis. In the same manner, phyllostictine A seems not to bind or bond with DNA as part of its mechanism of action. In contrast, phyllostictine A strongly reacts with GSH, which is a bionucleophile. The experimental data from the present study are in favor of a bonding process between GSH and phyllostictine A to form a complex though Michael attack at C=C bond at the acrylamide-like system. Considering the data obtained, two new hemisynthesized phyllostictine A derivatives together with three other natural phyllostictines (B, C and D) were also tested in vitro in five cancer cell lines. Compared to phyllostictine A, the two derivatives displayed a higher, phyllostictines B and D a lower, and phyllostictine C an almost equal, growth-inhibitory activity, respectively. These results led us to propose preliminary conclusions in terms of the structure-activity relationship (SAR) analyses for the anticancer activity of phyllostictine A and its related compounds, at least in vitro.
- OSTI ID:
- 21587778
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 254, Issue 1; Other Information: DOI: 10.1016/j.taap.2011.03.027; PII: S0041-008X(11)00131-1; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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