Protein Kinase Inhibitors from the Endophytic Fungus Alternaria sp. isolated from Polygonum senegalense Growing in Egypt

Abstract

Protein kinases, which function as components of signal transduction pathways, play a central role in diverse biological processes, such as control of cell growth, metabolism, differentiation, and apoptosis [1]. Identification of the key roles of protein kinases in cancer has led to extensive efforts to develop kinase inhibitors for the treatment of a wide range of cancers [2]. In continuation of our efforts to discover natural protein kinase inhibitors we studied extracts of liquid and rice cultures of the fungal endophyte Alternaria sp. isolated from the Egyptian medicinal plant Polygonum senegalense. Chromatographic separation of the extracts yielded the known compounds alternariol (1), alternariol 5-O-methyl ether (2), altenusin (3), 2,5-dimethyl-7-hydroxychromone (4), tenuazonic acid (5), altertoxin I (6), talaroflavone (7), and altenuene (8), in addition to seven new metabolites (9-15). The structures of the compounds were unambiguously established on the basis of NMR spectroscopic and mass spectrometric data. Compounds 1-3, 9, and 12 showed cytotoxic activity toward L5178Y mouse lymphoma cell line with EC50 values ranging from 1.7 to 7.8µg/mL. When analyzed in vitro for their inhibitory potential against 24 different protein kinases, compounds 1-3, 6, 9, and 11-13 inhibited several of these enzymes (IC50 values 0.22-9.8µg/mL).