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Synthesis and evaluation of 2,9-disubstituted 8-phenylthio/phenylsulfinyl-9H-purine as new EGFR inhibitors
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2018-03-16 , DOI: 10.1016/j.bmc.2018.03.025
Yuan-Yuan Hei , Ying Shen , Jin Wang , Hao Zhang , Hong-Yi Zhao , Minhang Xin , Yong-Xiao Cao , Yan Li , San-Qi Zhang

In present study, we described the synthesis and biological evaluation of a new class of EGFR inhibitors containing 2,9-disubstituted 8-phenylthio/phenylsulfinyl-9H-purine scaffold. Thirty-one compounds were synthesized. Among them, compound C9 displayed the IC50 of 29.4 nM against HCC827 cell line and 1.9 nM against EGFRL858R. Compound C12 showed moderate inhibitory activity against EGFRL858R/T790M/C797S (IC50 = 114 nM). Western bolt assay suggested that compound C9 significantly inhibited EGFR phosphorylation. In vivo test, compound C9 remarkably exhibited inhibitory effect on tumor growth at 5.0 mg/kg by oral administration in established nude mouse HCC827 xenograft model. These results indicate that the 2,9-disubstituted 8-phenylsulfinyl/phenylsulfinyl-9H-purine derivatives can act as potent EGFR(L858R) inhibitors and effective anticancer agents. Additionally, optimization of compound C12 may result in discovering the fourth-generation EGFR-TKIs.



中文翻译:

2,9-二取代的8-苯硫基/苯亚磺酰基-9 H-嘌呤作为新的EGFR抑制剂的合成和评价

在本研究中,我们描述了包含2,9-二取代的8-苯硫基/苯亚磺酰基-9 H-嘌呤支架的新型EGFR抑制剂的合成和生物学评估。合成了三十一种化合物。其中,化合物C9对HCC827细胞系的IC 50为29.4 nM,对EGFR L858R的IC 50为1.9 nM 。化合物C12显示出对EGFR L858R / T790M / C797S的中等抑制活性(IC 50  = 114 nM)。Western螺栓测定表明化合物C9显着抑制EGFR磷酸化。体内测试,化合物C9在已建立的裸鼠HCC827异种移植模型中,口服给药对5.0 mg / kg的肿瘤生长具有明显的抑制作用。这些结果表明,2,9-二取代的8-苯基亚磺酰基/苯基亚磺酰基-9 H-嘌呤衍生物可以作为有效的EGFR(L858R)抑制剂和有效的抗癌剂。另外,化合物C12的优化可能会导致发现第四代EGFR-TKI。

更新日期:2018-03-16
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