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Design, synthesis and structure-activity relationship of 1,8-naphthalimide derivatives as highly potent hCYP1B1 inhibitors

文献类型：期刊论文

作者Wei, Yueyue2,4; Xiong, Yuan3; Liao, Qingyi2,4; Yang, Ya3; Tian, Tian3; Guo, Xiqian1; Dong, Sanfeng2; Zhu, Jianming1; Zhang, Yong2; Li, Bo2
刊名BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
出版日期2024-07-15
卷号107页码:8
关键词8-naphthalimide Structure -activity relationships (SAR) Paclitaxel (PTX) resistance Molecular docking
ISSN号0960-894X
DOI10.1016/j.bmcl.2024.129776
通讯作者Zhu, Weiliang(wlzhu@simm.ac.cn) ; Ge, Guangbo(geguangbo@shutcm.edu.cn)
英文摘要Human cytochrome P450 1B1 enzyme (hCYP1B1), a member of hCYP1 subfamily, plays a crucial role in multiple diseases by participating in many metabolic pathways. Although a suite of potent hCYP1B1 inhibitors have been previously reported, most of them also act as aryl hydrocarbon receptor (AhR) agonists that can up -regulate the expression of hCYP1B1 and then counteract their inhibitory potential in living systems. This study aimed to develop novel efficacious hCYP1B1 inhibitors that worked well in living cells but without AhR agonist effects. For these purposes, a series of 1,8-naphthalimide derivatives were designed and synthesized, and their structureactivity relationships (SAR) as hCYP1B1 inhibitors were analyzed. Following three rounds SAR studies, several potent hCYP1B1 inhibitors were discovered, among which compound 3n was selected for further investigations owing to its extremely potent anti-hCYP1B1 activity (IC 50 = 0.040 nM) and its blocking AhR transcription activity in living cells. Inhibition kinetic analyses showed that 3n potently inhibited hCYP1B1 via a mix inhibition manner, showing a K i value of 21.71 pM. Docking simulations suggested that introducing a pyrimidine moiety to the hit compound ( 1d ) facilitated 3n to form two strong interactions with hCYP1B1/heme, viz. , the C-Br & ctdot;pi halogen bond and the N -Fe coordination bond. Further investigations demonstrated that 3n (5 mu M) could significantly reverse the paclitaxel (PTX) resistance in H460/PTX cells, evidenced by the dramatically reduced IC 50 values, from 632.6 nM (PTX alone) to 100.8 nM (PTX plus 3n ). Collectively, this study devised a highly potent hCYP1B1 inhibitor ( 3n ) without AhR agonist effect, which offered a promising drug candidate for overcoming hCYP1B1-associated drug resistance.
WOS关键词SELECTIVITY ; RESISTANCE ; EXPRESSION
资助项目National Key Research and Devel- opment Program of China[2022YFA1004304] ; National Natural Science Foundation of China[82322067] ; National Natural Science Foundation of China[82273897] ; National Natural Science Foundation of China[22277129] ; Shanghai Municipal Health Commission's TCM research project[2022CX005] ; Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine[ZYYCXTD-D-202004]
WOS研究方向Pharmacology & Pharmacy ; Chemistry
语种英语
WOS记录号WOS:001239540700001
出版者PERGAMON-ELSEVIER SCIENCE LTD
源URL[http://119.78.100.183/handle/2S10ELR8/311636]  
专题新药研究国家重点实验室
通讯作者Zhu, Weiliang; Ge, Guangbo
作者单位1.Shanghai Polytech Univ, Sch Resources & Environm Engn, Shanghai 201209, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Shanghai Univ Tradit Chinese Med, Inst Interdisciplinary Integrat Med Res, Shanghai Frontiers Sci Ctr TCM Chem Biol, Shanghai 201203, Peoples R China
4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210046, Peoples R China
推荐引用方式
GB/T 7714		 Wei, Yueyue,Xiong, Yuan,Liao, Qingyi,et al. Design, synthesis and structure-activity relationship of 1,8-naphthalimide derivatives as highly potent hCYP1B1 inhibitors[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,2024,107:8.
APA Wei, Yueyue.,Xiong, Yuan.,Liao, Qingyi.,Yang, Ya.,Tian, Tian.,...&Ge, Guangbo.(2024).Design, synthesis and structure-activity relationship of 1,8-naphthalimide derivatives as highly potent hCYP1B1 inhibitors.BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,107,8.
MLA Wei, Yueyue,et al."Design, synthesis and structure-activity relationship of 1,8-naphthalimide derivatives as highly potent hCYP1B1 inhibitors".BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 107(2024):8.

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来源：上海药物研究所

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