Design, synthesis and biological activity of novel 2,3,4,5-tetra-substituted thiophene derivatives as PI3Kα inhibitors with potent antitumor activity

被引：11

作者：

Liao, Weike ^{[1
]}

Wang, Zhongyuan ^{[2
]}

Han, Yufei ^{[3
]}

Qi, Yinliang ^{[3
]}

Liu, Jiaan ^{[5
]}

Xie, Juan ^{[2
]}

Tian, Ye ^{[3
]}

Lei, Qiancheng ^{[1
]}

Chen, Rui ^{[1
]}

Sun, Ming ^{[3
]}

Tang, Lei ^{[1
]}

Gong, Guowei ^{[4
]}

Zhao, Yanfang ^{[3
]}

机构：

[1] Guizhou Med Univ, Guizhou Prov Engn Technol Res Ctr Chem Drug R&D, State Key Lab Funct & Applicat Med Plants, Guiyang 550004, Peoples R China

[2] Guizhou Prov Peoples Hosp, Dept Pharm, Guiyang 550002, Peoples R China

[3] Shenyang Pharmaceut Univ, Minist Educ, Key Lab Struct Based Drug Design & Discovery, 103 Wenhua Rd, Shenyang 110016, Peoples R China

[4] Zunyi Med Univ, Dept Bioengn, Zhuhai Campus, Zhuhai 519041, Guangdong, Peoples R China

[5] Univ Massachusetts Amherst, Dept Chem, Amherst, MA 01003 USA

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 197卷

基金：

中国国家自然科学基金;

关键词：

PI3K alpha; Antiproliferative activities; Synthesis; 2,3,4,5-Tetra-substituted thiophene derivatives; PI3K INHIBITORS; DISCOVERY; PATHWAY; NVP-BYL719; TARGET;

D O I：

10.1016/j.ejmech.2020.112309

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Using a rational design strategy for isoform-selective inhibition of PI3K alpha, two series of novel 2,3,4,5-tetra-substituted thiophene derivatives containing either diaryl urea or N-Acylarylhydrazone scaffold were designed and synthesized. The most promising compound 12k was demonstrated to bear nanomolar PI3K alpha inhibitory potency with 12, 28, 30, 196-fold selectivity against isoforms beta, gamma, delta and mTOR. Besides, it also showed good developability profiles in cell-based proliferation against a panel of human tumor cells as well as ADME assays. We herein report on their design, synthesis, SAR and potential developability properties. (C) 2020 Elsevier Masson SAS. All rights reserved.

引用

页数：14

共 50 条

[31] Design,synthesis and antitumor activity of 3-substituted quinolone derivatives (Ⅰ)
Hua Wang Qi Dong You Zhi Yu Li Yi Quan Zou Department of Medicinal Chemistry
ChineseChemicalLetters, 2008, 19 (12) : 1395 - 1397
[32] Design, Synthesis, and Biological Evaluation of Substituted Pyrimidines as Potential Phosphatidylinositol 3-Kinase (PI3K) Inhibitors
Zhang, Ji-Quan
Luo, Yong-Jie
Xiong, Yan-Shi
Yu, Yang
Tu, Zheng-Chao
Long, Zi-Jie
Lai, Xiao-Ju
Chen, Hui-Xuan
Luo, Yu
Weng, Jiang
Lu, Gui
JOURNAL OF MEDICINAL CHEMISTRY, 2016, 59 (15) : 7268 - 7274
[33] Synthesis and biological evaluation of 4-(piperid-3-yl)amino substituted 6-pyridylquinazolines as potent PI3Kδ inhibitors
Feng, Yifan
Duan, Weiming
Fan, Shu
Zhang, Hao
Zhang, San-Qi
Xin, Minhang
BIOORGANIC & MEDICINAL CHEMISTRY, 2019, 27 (19)
[34] Discovery of fluoroquinolone derivatives as potent, selective inhibitors of PI3Kγ
Sha, Shao
Han, Hong-Wei
Gao, Fei
Liu, Tian-Bao
Li, Zhen
Xu, Chi
Zhong, Wei-Qing
Zhu, Hai-Liang
MEDCHEMCOMM, 2015, 6 (11) : 2029 - 2035
[35] Design, Synthesis, Biological Evaluation, and Molecular Modeling of 2-Difluoromethylbenzimidazole Derivatives as Potential PI3Kα Inhibitors
Wang, Xiangcong
Zhang, Moxuan
Zhu, Ranran
Wu, Zhongshan
Wu, Fanhong
Wang, Zhonghua
Yu, Yanyan
MOLECULES, 2022, 27 (02):
[36] Design, synthesis, and biological evaluation of 2,4-dimorpholinopyrimidine-5-carbonitrile derivatives as orally bioavailable PI3K inhibitors
Huang, Daowei
Yang, Jixia
Zhang, Qingwei
Zhou, Xiaolei
Wang, Yanbo
Shang, Zhenhua
Li, Jianqi
Zhang, Baoyin
FRONTIERS IN PHARMACOLOGY, 2024, 15
[37] Design, synthesis and biological evaluation of novel selective PI3Kδ inhibitors containing pyridopyrimidine scaffold
Ma, Mengyan
Feng, Yifan
Zhang, San-Qi
Duan, Weiming
Gao, Li
Yuan, Bo
Xin, Minhang
FUTURE MEDICINAL CHEMISTRY, 2023, 15 (16) : 1491 - 1509
[38] Design, synthesis, and biological evaluation of novel bivalent PI3K inhibitors for the potential treatment of cancer
Xia, Liang
Jiang, Lin
Du, Tingting
Lin, Songwen
Xiong, Tianning
Peng, Shouguo
Tian, Hua
Zhang, Kehui
Wu, Deyu
Sheng, Li
Ji, Ming
Chen, Xiaoguang
Xu, Heng
BIOORGANIC CHEMISTRY, 2023, 140
[39] Synthesis and biological evaluation of novel 2-arylamino-3-(arylsulfonyl)quinoxalines as PI3Kα inhibitors
Wu, Peng
Su, Yi
Liu, Xiaowen
Zhang, Lei
Ye, Yong
Xu, Jianchao
Weng, Shaoyu
Li, Yani
Liu, Tao
Huang, Shufang
Yang, Bo
He, Qiaojun
Hu, Yongzhou
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2011, 46 (11) : 5540 - 5548
[40] Design, synthesis and antitumor activity of 3-substituted quinolone derivatives (I)
Wang, Hua
You, Qi Dong
Li, Zhi Yu
Zou, Yi Quan
CHINESE CHEMICAL LETTERS, 2008, 19 (12) : 1395 - 1397

← 1 2 3 4 5 →