Clavilactones, a novel class of tyrosine kinase inhibitors of fungal origin
Section snippets
Clavilactones
The benzoquinoid macrolide structure of clavilactones under study is reported in Table 1. On the basis of the oxidation status of the aromatic ring, these molecules can be assigned to one of two groups, the first including the quinone derivatives CB and CD and the second the hydroquinones CA, dimethyl-CA, and diacetyl-CA. CA, CB, and CD were extracted from the C. clavipes culture medium as previously described 27, 28. Dimethyl-CA and diacetyl-CA are semisynthetic derivatives [28]. CA and CB
Antiproliferative activity of clavilactones towards tumor and oncogene-transformed cell lines
We focused on EGF-R and the Ret/ptc1 oncoprotein as possible target tyrosine kinases. To select inhibitory compounds, we adopted a cell and mechanism-based approach previously described 41, 42. As first step of the screening, we compared the antiproliferative activity profile of test compounds against a variety of cell lines characterized by differential expression of these two enzymes. The antiproliferative effects of clavilactones after 96-hr incubation of the three human cell lines A431,
Discussion
In an attempt to identify novel natural inhibitors of protein tyrosine kinases, we evaluated the three fungal metabolites, clavilactones CA, CB, and CD, and the two semisynthetic derivatives, diacetyl- and dimethyl-CA (structures in Table 1) 27, 28, by a cell and mechanism-based approach which previously allowed the identification of a new EGF-R inhibitor [41] and inhibitors of the Ret/ptc1 oncoprotein [42]. The comparison of the antiproliferative activity of these compounds against cell lines
Acknowledgements
We are grateful to Professor Lucio Merlini, Dr. Sergio Penco, and Dr. Giuseppe Cassinelli for helpful suggestions. NIH3T3PTC1 cells, NIH3T3H-RAS cells, and the anti-ret antibody were kindly provided by Dr. Marco A. Pierotti and NIH3T3HER1 cells by Dr. Elda Tagliabue. The expert technical assistance of Mr. Mario Azzini is acknowledged. This work was supported by the Ministero della Sanità, the Italy-USA Program on “Therapy of Tumors”, and the CNR (PF ACRO).
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