Design of hypoxia-targeting protein tyrosine kinase inhibitor using an innovative pharmacophore 2-methylene-4-cyclopentene-1,3-dione
Design of hypoxia-targeting protein tyrosine kinase inhibitor using an innovative pharmacophore 2-methylene-4-cyclopentene-1,3-dione
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DOI：
10.1016/j.bbapap.2003.11.011
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发表时间：
2004-03-11
影响因子：
3.2
通讯作者：
Shimamura, M
中科院分区：
文献类型：
--
作者：
Hori, H;Nagasawa, H;Shimamura, M
我们在这份报告中审查我们的战略和战术设计2-羟基亚芳基-4-环戊烯-1，3-二酮作为蛋白酪氨酸激酶（PTK）抑制剂具有低线粒体毒性和/或低氧靶向功能。我们的合成设计基于一个创新的药效团，2-亚甲基-4-环戊烯-1，3-二酮。我们首先证明了这种药效团在2-亚甲基-4-环戊烯-1的开发中的有效性，我们的结果表明，环戊烯二酮衍生的TX-1123是更有效的抗肿瘤酪氨酸磷酸酶抑制剂，并且还显示出比丙二腈衍生的AG 17更低的线粒体毒性。1123（TX-1925）保留了其酪氨酸磷酸酶样性质。包括线粒体毒性和抗肿瘤活性。然而，AG 17的甲基化产物（TX-1927）保留了其酪氨酸磷酸化样抗肿瘤活性，但失去了其线粒体毒性。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价表明，PTK抑制剂TX-1123和TX-1925是比酪氨酸磷酸化抑制剂AGIT更有希望的抗肿瘤药物候选物。其次，作为对这种4-环戊烯-1，3-二酮作为创新药效团的有希望的能力的进一步研究，我们讨论了我们开发缺氧靶向PTK抑制剂TX 1123类似物的策略。2 -硝基咪唑-氨基亚甲基环戊烯二酮，如TX-2036，用于癌症治疗，特别是用于具有高水平缺氧的胰腺癌。(C)2003 Elsevier B. V.保留所有权利。
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 tyiphostin 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 thatPTK inhibitors TX-1123 and TX-1925 are more promising candidates for antitumor agents than tyrphostin AGIT 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 TX1123 analogues. 2 -nitroimidazole-aminomethylenecyclopentenediones, such as TX-2036, for cancer treatment, especially for pancreatic cancers, which have a high level of hypoxia. (C) 2003 Elsevier B.V. All rights reserved.