Synthesis and evaluation of 2,9-disubstituted 8-phenylthio/phenylsulfinyl-9H-purine as new EGFR inhibitors |
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Authors: | Yuan-Yuan Hei Ying Shen Jin Wang Hao Zhang Hong-Yi Zhao Minhang Xin Yong-Xiao Cao Yan Li San-Qi Zhang |
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Affiliation: | 1. Department of Medicinal Chemistry, School of Pharmacy, Xi’an Jiaotong University, Xi’an, Shaanxi 710061, PR China;2. Department of Pharmacology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi 710061, PR China |
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Abstract: | 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. |
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Keywords: | Purine EGFR-TK inhibitor Drug design Antiproliferative effects Anticancer agent |
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