Design, synthesis and biological evaluation of substituted pyrrolo[2,3-d] pyrimidines as multiple receptor tyrosine kinase inhibitors and antiangiogenic agents
Design, synthesis and biological evaluation of substituted pyrrolo[2,3-d] pyrimidines as multiple receptor tyrosine kinase inhibitors and antiangiogenic agents
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DOI：
10.1016/j.bmc.2008.04.019
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发表时间：
2008-05-15
影响因子：
3.5
通讯作者：
Warnke, Linda A.
中科院分区：
文献类型：
--
作者：
Gangjee, Aleem;Namjoshi, Ojas A.;Warnke, Linda A.
受体酪氨酸激酶（receptor tyrosine kinases，RTK）直接或间接参与肿瘤的生长和转移，是肿瘤治疗的理想靶点。最近已经证明了从抑制单个RTK到抑制多个RTK的范式转变。我们设计并合成了八种N（4）-苯基取代的-6-（2-苯乙基取代的）-7H-吡咯并[2，3-d]嘧啶-2，4-二胺，作为我们之前发表的RTK抑制剂的同源系列。我们认为这会增加。决定效力和选择性的侧链柔性将改善RTK抑制谱。这些化合物是使用双亲电环化反应合成的，得到取代的吡咯并[2，3-d]嘧啶，然后氯化并在4-位用各种苯胺取代。Gangjee等人先前报道了该系列的另外五种化合物。(1)只针对IGFR的活动。本研究首次报道了它们的合成、表征及其对多种其他RTK的生物活性。在全细胞测定中的生物学评价显示，几种类似物对上皮生长因子受体（EGFR）、血管内皮生长因子受体-1（VEGFR-1）、血小板衍生生长因子受体-β（PDGFR-β）、培养物中A431细胞的生长以及鸡胚绒毛尿囊膜（CAM）血管生成测定具有显著的抑制活性。本研究中对RTK的抑制数据表明，这些类似物的6-乙基芳基取代基以及N（4）-苯基取代基的变化确实控制了对RTK的抑制活性的效力和特异性。此外，6-取代基的链长从亚甲基到乙基的同源化增加了RTK抑制谱。新的多RTK抑制剂（8，12）和有效的血管生成抑制剂（15，19）与最佳化合物N（4）-（3-三氟甲基苯基）-6-（2-苯乙基）-7H-吡咯并[2，3-d]嘧啶-2，4-二胺（15）一起鉴定，在CAM血管生成抑制试验中IC（50）值为30 nM。(C)2008爱思唯尔有限公司保留所有权利。
Direct and indirect involvement of receptor tyrosine kinases (RTKs) in tumor growth and metastasis makes them ideal targets for anticancer therapy. A paradigm shift from inhibition of single RTK to inhibition of multiple RTKs has been recently demonstrated. We designed and synthesized eight N(4)-phenylsubstituted-6-(2-phenylethylsubstituted)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamines as homologated series of our previously published RTK inhibitors. We reasoned that increased. flexibility of the side chain, which determines potency and selectivity, would improve the spectrum of RTK inhibition. These compounds were synthesized using a bis-electrophilic cyclization to afford substituted pyrrolo[2,3-d]pyrimidines followed by chlorination and substitution at the 4-position with various anilines. Five additional compounds of this series were previously reported by Gangjee et al.(1) with activities against IGFR only. Their synthesis, characterization and biological activities against a variety of other RTKs are reported in this study for the first time. The biological evaluation, in whole cell assays, showed several analogs had remarkable inhibitory activity against epithelial growth factor receptor ( EGFR), vascular endothelial growth factor receptor-1 (VEGFR-1), platelet-derived growth factor receptor-beta (PDGFR-beta), the growth of A431 cells in culture, and in the chicken embryo chorioallantoic membrane ( CAM) angiogenesis assay. The inhibitory data against the RTKs in this study demonstrate that variation of the 6-ethylaryl substituents as well as the N(4)-phenyl substituents of these analogs does indeed control both the potency and specificity of inhibitory activity against RTKs. In addition, homologation of the chain length of the 6-substituent from a methylene to an ethyl increases the spectrum of RTK inhibition. New multi-RTK inhibitors ( 8, 12) and potent inhibitors of angiogenesis ( 15, 19) were identified with the best compound,N(4)-(3-trifluromethylphenyl)-6-(2-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (15), with an IC(50) value of 30 nM in the CAM angiogenesis inhibition assay. (C) 2008 Elsevier Ltd. All rights reserved.