4-氨基喹唑啉衍生物作为EGF受体相关酪氨酸激酶活性抑制剂的合成及其抗增殖性能。

Anti-cancer drug design Pub Date : 1998-12-01
E Bouey-Bencteux, C Loison, N Pommery, R Houssin, J P Hénichart
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引用次数: 0

摘要

EGF的有丝分裂作用是由配体诱导的EGF受体(EGF- r)的自磷酸化介导的,EGF受体在许多人类癌症中通常过表达。因此,受体酪氨酸激酶(RTK)活性抑制剂可以被认为是有效的潜在抗肿瘤药物。为此,我们制备了4-氨基喹唑啉衍生物,并评估了它们抑制RTK活性和EGF-R自磷酸化的能力。此外,还对A431细胞生长进行了实验,以评估其抗增殖作用。结果表明,喹唑啉环4位的取代基一定是芳香胺,在苯基环3-(或2-)位上携带亲脂性吸电子基团。如果连接基团受到构象限制,例如与哌嗪的连接基团,则该芳香部分可能远离喹唑啉。亲水性和非芳香族取代基,如啉,得到完全无活性的化合物。在2,4-二氨基喹唑啉或三环化合物中,在喹唑啉环的2位处引入散装导致非活性产物。本研究报道了一系列具有良好特征的额外结构-活性关系,以开发新的egf - r相关酪氨酸激酶活性抑制剂。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Synthesis and antiproliferative properties of 4-aminoquinazoline derivatives as inhibitors of EGF receptor-associated tyrosine kinase activity.

The mitogenic action of EGF is mediated by ligand-induced autophosphorylation of the EGF receptor (EGF-R), which is commonly overexpressed in numerous human cancers. Inhibitors of receptor tyrosine kinase (RTK) activity could therefore be considered as effective potential antitumor agents. For this purpose, 4-aminoquinazoline derivatives were prepared and evaluated for their ability to inhibit RTK activity and the autophosphorylation of EGF-R. In addition, these compounds were tested on A431 cell growth to estimate their antiproliferative effect. The results showed that the substituent at the 4-position of the quinazoline ring must be an aromatic amine carrying small lipophilic electron-withdrawing groups on the 3- (or 2-) position of the phenyl ring. This aromatic moiety might be far from the quinazoline provided that the linking group is conformationally restricted, such as with piperazine. Hydrophilic and non-aromatic substituents such as morpholine gave completely inactive compounds. Introduction of a bulk at the 2-position of the quinazoline ring in 2,4-diaminoquinazolines or tricyclic compounds led to inactive products. This study reports additional structure-activity relationships of a well-characterized series to develop new inhibitors of EGF-R-associated tyrosine kinase activity.

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