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首页> 外文期刊>Biochimica et biophysica acta: BBA: International journal of biochemistry, biophysics and molecular biololgy. Proteins and Proteomics >Design of hypoxia-targeting protein tyrosine kinase inhibitor using an innovative pharmacophore 2-methylene-4-cyclopentene-1,3-dione
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Design of hypoxia-targeting protein tyrosine kinase inhibitor using an innovative pharmacophore 2-methylene-4-cyclopentene-1,3-dione

机译：使用新型药效团2-亚甲基-4-环戊烯-1,3-二酮设计靶向低氧的蛋白酪氨酸激酶抑制剂

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摘要

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.
机译：我们在这份报告中审查了我们的策略和策略，设计2-羟基亚芳基-4-环戊烯-1,3-二酮作为具有低线粒体毒性和/或低氧靶向功能的蛋白酪氨酸激酶（PTK）抑制剂。我们的合成设计基于创新的药效团2-亚甲基-4-环戊烯-1,3-二酮。我们首先显示了该药效团在开发2-亚甲基-4-环戊烯-1,3-二酮作为PTK抑制剂方面的有效性，该抑制剂比有效的PTK抑制剂tyrphostin AG17具有更低的线粒体毒性。我们的结果表明，环戊二烯衍生的TX-1123是一种更有效的抗肿瘤酪氨酸抑制剂，并且比丙二腈衍生的AG17的线粒体毒性更低。 TX-1123（TX-1925）的O-甲基化产物保留了其tyrphostin样的特性，包括线粒体毒性和抗肿瘤活性。但是，AG17（TX-1927）的甲基化产物保留了其酪氨酸受体样的抗肿瘤活性，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tyrphostin AG17更可能用作抗肿瘤药物。其次，作为对该4-环戊烯-1,3-二酮作为创新药效基团的有前途潜力的进一步研究，我们讨论了开发靶向低氧的PTK抑制剂TX-1123类似物2-硝基咪唑-氨基亚甲基环戊二酮等的策略。作为TX-2036，用于低氧水平高的癌症治疗，尤其是胰腺癌。

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