title: TX-1123: an antitumor 2-hydroxyarylidene-4-cyclopentene-1,3-dione as a protein tyrosine kinase inhibitor having low mitochondrial toxicity.
abstract: A series of 2-hydroxyarylidene-4-cyclopentene-1,3-diones were designed, synthesized, and evaluated with respect to protein tyrosine kinase (PTK) inhibition, mitochondrial toxicity, and antitumor activity. 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, a potent antitumor tyrphostin. 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 protein tyrosine kinase 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.
authors.affiliation: Department of Biological Science & Technology, Faculty of Engineering, The University of Tokushima, Tokushima, 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: Masaki
authors.initials: M
authors.lastname: Ishibashi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Uto
authors.forename: Akihiko
authors.initials: A
authors.lastname: Hirata
authors.forename: Kouichi
authors.initials: K
authors.lastname: Saijo
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
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D001597:Benzylidene Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002455:Cell Division / Q000187:drug effects; D003517:Cyclopentanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D054736:Elongation Factor 2 Kinase; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
chemical_list: C475851:2-hydroxyarylidene-4-cyclopentene-1,3-dione; D000970:Antineoplastic Agents; D001597:Benzylidene Compounds; D003517:Cyclopentanes; D004791:Enzyme Inhibitors; C007201:cyclopentanone; C517689:EEF2K protein, human; D011505:Protein-Tyrosine Kinases; D019061:src-Family Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D054736:Elongation Factor 2 Kinase