Synthesis and evaluation of 2,9-disubstituted 8-phenylthio/phenylsulfinyl-9H-purine as new EGFR inhibitors

Yuan Yuan Hei; Ying Shen; Jin Wang; Hao Zhang; Hong Yi Zhao; Minhang Xin; Yong Xiao Cao; Yan Li; San Qi Zhang

doi:10.1016/j.bmc.2018.03.025

Synthesis and evaluation of 2,9-disubstituted 8-phenylthio/phenylsulfinyl-9H-purine as new EGFR inhibitors

Yuan Yuan Hei
, Ying Shen
, Jin Wang
, Hao Zhang
, Hong Yi Zhao
, Minhang Xin
, Yong Xiao Cao
, Yan Li
, San Qi Zhang

Health Science Center

Xi'an Jiaotong University

Research output: Contribution to journal › Article › peer-review

39 Scopus citations

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 EGFR^L858R. Compound C12 showed moderate inhibitory activity against EGFR^{L858R/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.

Original language	English
Pages (from-to)	2173-2185
Number of pages	13
Journal	Bioorganic and Medicinal Chemistry
Volume	26
Issue number	8
DOIs	https://doi.org/10.1016/j.bmc.2018.03.025
State	Published - 1 May 2018

Keywords

Anticancer agent
Antiproliferative effects
Drug design
EGFR-TK inhibitor
Purine

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@article{43ee8a0991684bfda5126fc318ceb952,

title = "Synthesis and evaluation of 2,9-disubstituted 8-phenylthio/phenylsulfinyl-9H-purine as new EGFR inhibitors",

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.",

keywords = "Anticancer agent, Antiproliferative effects, Drug design, EGFR-TK inhibitor, Purine",

author = "Hei, \{Yuan Yuan\} and Ying Shen and Jin Wang and Hao Zhang and Zhao, \{Hong Yi\} and Minhang Xin and Cao, \{Yong Xiao\} and Yan Li and Zhang, \{San Qi\}",

note = "Publisher Copyright: {\textcopyright} 2018 Elsevier Ltd",

year = "2018",

month = may,

day = "1",

doi = "10.1016/j.bmc.2018.03.025",

language = "英语",

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AU - Hei, Yuan Yuan

AU - Shen, Ying

AU - Wang, Jin

AU - Zhang, Hao

AU - Zhao, Hong Yi

AU - Xin, Minhang

AU - Cao, Yong Xiao

AU - Li, Yan

AU - Zhang, San Qi

PY - 2018/5/1

Y1 - 2018/5/1

N2 - 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.

AB - 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.

KW - Anticancer agent

KW - Antiproliferative effects

KW - Drug design

KW - EGFR-TK inhibitor

KW - Purine

UR - https://www.scopus.com/pages/publications/85044297910

U2 - 10.1016/j.bmc.2018.03.025

DO - 10.1016/j.bmc.2018.03.025

M3 - 文章

C2 - 29576272

AN - SCOPUS:85044297910

SN - 0968-0896

VL - 26

SP - 2173

EP - 2185

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 8

ER -

Synthesis and evaluation of 2,9-disubstituted 8-phenylthio/phenylsulfinyl-9H-purine as new EGFR inhibitors

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Keywords

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