Hori Hitoshi, Nagasawa Hideko, Ishibashi Masaki, Uto Yoshihiro, Hirata Akihiko, Saijo Kouichi, Ohkura Kazuto, Kirk Kenneth L, Uehara Yoshimasa
Department of Biological Science & Technology, Faculty of Engineering, The University of Tokushima, Tokushima, Japan.
Bioorg Med Chem. 2002 Oct;10(10):3257-65. doi: 10.1016/s0968-0896(02)00160-8.
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.
设计、合成了一系列2-羟基亚苄基-4-环戊烯-1,3-二酮，并对其蛋白酪氨酸激酶（PTK）抑制作用、线粒体毒性和抗肿瘤活性进行了评估。我们的结果表明，环戊二酮衍生的TX-1123是一种更有效的抗肿瘤酪氨酸磷酸化抑制剂，并且与丙二腈衍生的强效抗肿瘤酪氨酸磷酸化抑制剂AG17相比，其线粒体毒性更低。TX-1123的O-甲基化产物（TX-1925）保留了其类酪氨酸磷酸化抑制剂的特性，包括线粒体毒性和抗肿瘤活性。然而，AG17的甲基化产物（TX-1927）保留了其类酪氨酸磷酸化抑制剂的抗肿瘤活性，但失去了线粒体毒性。我们对这些药物在蛋白酪氨酸激酶抑制、线粒体抑制、抗肿瘤活性和肝毒性方面的综合评估表明，PTK抑制剂TX-1123和TX-1925比酪氨酸磷酸化抑制剂AG17更有希望成为抗肿瘤药物候选物。
