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

Abstract

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.

• Authors: Hitoshi Hori, Hideko Nagasawa, Yoshihiro Uto, Kazuto Ohkura, Kenneth L Kirk, Yoshimasa Uehara, Mariko Shimamura
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1697 Issue 1-2 Pg. 29-38 (Mar 11 2004) ISSN: 0006-3002 [Print] Netherlands
• PMID: 15023348 (Publication Type: Journal Article, Review)

Chemical References

• 2-hydroxyarylidene-4-cyclopentene-1,3-dione
• Antineoplastic Agents
• Benzylidene Compounds
• Cyclopentanes
• Enzyme Inhibitors
• Nitriles
• Tyrphostins
• SF 6847
• Protein-Tyrosine Kinases

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Benzylidene Compounds (chemistry, pharmacology, toxicity)
• Cell Hypoxia (drug effects, physiology)
• Cyclopentanes (chemistry, pharmacology, toxicity)
• Drug Design
• Enzyme Inhibitors (chemistry, pharmacology, toxicity)
• Humans
• Mitochondria (drug effects)
• Models, Molecular
• Nitriles
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Structure-Activity Relationship
• Tyrphostins (chemistry, pharmacology, toxicity)