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Biochim Biophys Acta. 2004 Mar 11;1697(1-2):29-38.

Design of hypoxia-targeting protein tyrosine kinase inhibitor using an innovative pharmacophore 2-methylene-4-cyclopentene-1,3-dione.

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Department of Biological Science and Technology, Faculty of Engineering, The University of Tokushima, Minamijosanjimacho-2, Tokushima 770-8506, Japan.


We review in this report our strategy and tactics for the design of 2-hydroxyarylidene-4-cyclopentene-1,3-diones as protein tyrosine kinase (PTK) inhibitors having low mitochondrial toxicities and/or hypoxia-targeting function. We based our synthetic design on an innovative pharmacophore, 2-methylene-4-cyclopentene-1,3-dione. We first showed the effectiveness of this pharmacophore in the development of 2-methylene-4-cyclopentene-1,3-dione as PTK inhibitor that have lower mitochondrial toxicity than the potent PTK inhibitor tyrphostin AG17. Our results show that the cyclopentenedione-derived TX-1123 is a more potent antitumor tyrphostin and also shows lower mitochondrial toxicity than the malononitrile-derived AG17. The O-methylation product of TX-1123 (TX-1925) retained its tyrphostin-like properties, including mitochondrial toxicity and antitumor activities. However, the methylation product of AG17 (TX-1927) retained its tyrphostin-like antitumor activities, but lost its mitochondrial toxicity. Our comprehensive evaluation of these agents with respect to PTK inhibition, mitochondrial inhibition, antitumor activity, and hepatotoxicity demonstrates that PTK inhibitors TX-1123 and TX-1925 are more promising candidates for antitumor agents than tyrphostin AG17. Secondly, as a further investigation of the promising power of this 4-cyclopentene-1,3-dione as an innovative pharmacophore, we discuss our strategy of development of hypoxia-targeting PTK inhibitor TX-1123 analogues, 2-nitroimidazole-aminomethylenecyclopentenediones, such as TX-2036, for cancer treatment, especially for pancreatic cancers, which have a high level of hypoxia.

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