title: 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.affiliation: Department of Biological Science and Technology, Faculty of Engineering, The University of Tokushima, Minamijosanjimacho-2, Tokushima 770-8506, Japan. hori@bio.tokushima-u.ac.jp
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hori
authors.forename: Hideko
authors.initials: H
authors.lastname: Nagasawa
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Uto
authors.forename: Kazuto
authors.initials: K
authors.lastname: Ohkura
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Kirk
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Uehara
authors.forename: Mariko
authors.initials: M
authors.lastname: Shimamura
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001597:Benzylidene Compounds / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D015687:Cell Hypoxia / Q000187:drug effects* / Q000502:physiology; D003517:Cyclopentanes / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D008928:Mitochondria / Q000187:drug effects; D008958:Models, Molecular; D009570:Nitriles; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D020032:Tyrphostins / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity
chemical_list: C475851:2-hydroxyarylidene-4-cyclopentene-1,3-dione; D000970:Antineoplastic Agents; D001597:Benzylidene Compounds; D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D009570:Nitriles; D020032:Tyrphostins; C001784:SF 6847; D011505:Protein-Tyrosine Kinases