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

[21] Identification of Novel Piperazinylquinoxaline Derivatives as Potent Phosphoinositide 3-Kinase (PI3K) Inhibitors
Wu, Peng
Su, Yi
Guan, Xianghong
Liu, Xiaowen
Zhang, Jiankang
Dong, Xiaowu
Huang, Wenhai
Hu, Yongzhou
PLOS ONE, 2012, 7 (08):
[22] Discovery and biological evaluation of novel pyrazolopyridine derivatives as potent and orally available PI3Kδ inhibitors
Hamajima, Toshihiro
Takahashi, Fumie
Kato, Koji
Mukoyoshi, Koichiro
Yoshihara, Kousei
Yamaki, Susumu
Sugano, Yukihito
Moritomo, Ayako
Yamagami, Kaoru
Yokoo, Koji
Fukahori, Hidehiko
BIOORGANIC & MEDICINAL CHEMISTRY, 2018, 26 (09) : 2410 - 2419
[23] Design, Synthesis, and Biological Evaluation of Sulfonamide Methoxypyridine Derivatives as Novel PI3K/mTOR Dual Inhibitors
Gao, Haotian
Li, Zaolin
Wang, Kai
Zhang, Yuhan
Wang, Tong
Wang, Fang
Xu, Youjun
PHARMACEUTICALS, 2023, 16 (03)
[24] Synthesis and biological evaluation of 3-(piperidin-4-yl)isoxazolo[4,5-d]pyrimidine derivatives as novel PI3Kδ inhibitors
Guo, Jia-Lin
Liu, Yun-Yong
Pei, Ya-Zhong
CHINESE CHEMICAL LETTERS, 2015, 26 (10) : 1283 - 1288
[25] Design, synthesis and in vitro biological evaluation of 2-aminopyridine derivatives as novel PI3Kδ inhibitors for hematological cancer
Yang, Chengbin
Gong, Yimin
Gao, Yunjian
Deng, Mingli
Liu, Xiaofeng
Yang, Yongtai
Ling, Yun
Jia, Yu
Zhou, Yaming
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2023, 82
[26] Combination of PI3K/mTOR Inhibitors: Antitumor Activity and Molecular Correlates
Mazzoletti, Marco
Bortolin, Francesca
Brunelli, Laura
Pastorelli, Roberta
Di Giandomenico, Silvana
Erba, Eugenio
Ubezio, Paolo
Broggini, Massimo
CANCER RESEARCH, 2011, 71 (13) : 4573 - 4584
[27] Design, synthesis, and biological activity of novel tetrahydropyrazolopyridone derivatives as FXa inhibitors with potent anticoagulant activity
Sun, Xiaoqing
Hong, Zexin
Liu, Moyi
Guo, Su
Yang, Di
Wang, Yong
Lan, Tian
Gao, Linyu
Qi, Hongxia
Gong, Ping
Liu, Yajing
BIOORGANIC & MEDICINAL CHEMISTRY, 2017, 25 (10) : 2800 - 2810
[28] Design, Synthesis and Biological Activity of Novel Substituted Diamides Derivatives Containing Thiophene Ring
Li Lin
Li Miao
Chai Baoshan
Yang Jichun
Song Yuquan
Liu Changling
CHEMICAL JOURNAL OF CHINESE UNIVERSITIES-CHINESE, 2016, 37 (09): : 1649 - 1654
[29] Design, synthesis and biological evaluation of novel benzothiadiazine derivatives as potent PI3Kδ-selective inhibitors for treating B-cell-mediated malignancies
Ma, Xiaodong
Wei, Jun
Wang, Chang
Gu, Dongyan
Hu, Yongzhou
Sheng, Rong
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2019, 170 : 112 - 125
[30] Discovery of 5-Phenylthiazol-2-amine Derivatives as Novel PI4KIIIβ Inhibitors with Efficacious Antitumor Activity by Inhibiting the PI3K/AKT Axis
Wang, Bichuan
Hao, Siyuan
Han, Fang
Wu, Tianzhi
Jia, Shuolei
Ruan, Xiuqin
Zhou, Qingfa
JOURNAL OF MEDICINAL CHEMISTRY, 2025, 68 (06) : 6270 - 6291

← 1 2 3 4 5 →