Hori Hitoshi, Nagasawa Hideko, Uto Yoshihiro, Ohkura Kazuto, Kirk Kenneth L, Uehara Yoshimasa, Shimamura Mariko
Department of Biological Science and Technology, Faculty of Engineering, The University of Tokushima, Minamijosanjimacho-2, Tokushima 770-8506, Japan.
Biochim Biophys Acta. 2004 Mar 11;1697(1-2):29-38. doi: 10.1016/j.bbapap.2003.11.011.
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.
在本报告中，我们回顾了将2-羟基亚苄基-4-环戊烯-1,3-二酮设计为具有低线粒体毒性和/或低氧靶向功能的蛋白质酪氨酸激酶（PTK）抑制剂的策略和方法。我们的合成设计基于一种创新的药效基团——2-亚甲基-4-环戊烯-1,3-二酮。我们首先证明了该药效基团在开发2-亚甲基-4-环戊烯-1,3-二酮作为PTK抑制剂方面的有效性，其线粒体毒性低于强效PTK抑制剂 tyrphostin AG17。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，并且其线粒体毒性也低于丙二腈衍生的AG17。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PTK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。其次，作为对这种4-环戊烯-1,3-二酮作为创新药效基团的潜力的进一步研究，我们讨论了开发用于癌症治疗，特别是用于缺氧程度高的胰腺癌的低氧靶向PTK抑制剂TX-1123类似物——2-硝基咪唑-氨基亚甲基环戊二酮（如TX-2036）的策略。
