Exploration of novel phthalazinone derivatives as potential efflux transporter inhibitors for reversing multidrug resistance and improving the oral absorption of paclitaxel

作者全名："Shi, Wei; Zhang, Ping; Zou, Feng; Zhou, Jiaqi; Yin, Ziyu; Cai, Zilong; Ghaleb, Hesham; Jiang, Yuxuan; Huang, Wenlong; Liu, Yan; Qiu, Qianqian; Qian, Hai"

作者地址："[Shi, Wei; Zhang, Ping; Zou, Feng; Zhou, Jiaqi; Yin, Ziyu; Cai, Zilong; Ghaleb, Hesham; Jiang, Yuxuan; Huang, Wenlong; Qiu, Qianqian; Qian, Hai] China Pharmaceut Univ, Ctr Drug Discovery, State Key Lab Nat Medicines, 24 Tongjiaxiang, Nanjing 210009, Peoples R China; [Huang, Wenlong; Qian, Hai] China Pharmaceut Univ, Jiangsu Key Lab Drug Discovery Metab Dis, 24 Tongjiaxiang, Nanjing 210009, Peoples R China; [Liu, Yan] Chongqing Med Univ, Sch Pharm, Chongqing 400016, Peoples R China"

通信作者："Qiu, QQ; Qian, H (通讯作者)，China Pharmaceut Univ, Ctr Drug Discovery, State Key Lab Nat Medicines, 24 Tongjiaxiang, Nanjing 210009, Peoples R China.; Qian, H (通讯作者)，China Pharmaceut Univ, Jiangsu Key Lab Drug Discovery Metab Dis, 24 Tongjiaxiang, Nanjing 210009, Peoples R China.; Liu, Y (通讯作者)，Chongqing Med Univ, Sch Pharm, Chongqing 400016, Peoples R China."

来源：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

ESI学科分类：CHEMISTRY

WOS号：WOS:000891539300005

JCR分区：Q1

影响因子：6.7

年份：2022

卷号：233

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Efflux transporter; Multidrug resistance; P-gp; BCRP; Oral bioavailability

摘要："Chemotherapy is an important means of cancer treatment. However, overexpression of efflux transporters (including but not limited to P-gp and BCRP) can lead to resistance to cancer chemotherapy. Multiple-target inhibitors of efflux transporter can be overcome the resistance and improve the oral bioavailability of chemotherapy drugs. Therefore, we designed and synthesized a series of phthalazinone ring derivatives (1-20) with different aromatic heterocycles substituents on the amide bond for dual inhibition of P-gp and BCRP. Most target compounds significantly increased the accumulation of P-gp substrates in the chemo-resistant cancer cell lines by inhibiting the efflux of transporters. Compound 19 in particular showed stronger MDR reversal compared to Gefitinib and Verapamil, and comparable to that of the BCRP inhibitor Ko143. In addition, compound 19 improved intestinal absorption of paclitaxel (PTX) and enhanced the bioavailability of the orally administered drug in vivo. (c) 2022 Elsevier Masson SAS. All rights reserved."

基金机构："National Science Foundation of China [81872733, 81872734, 81803353]; China Postdoctoral Science Foundation [2020M681792]; Research & Development Project in Key Areas of Guangdong Province [2019B020203003]"

基金资助正文："We thank the National Science Foundation of China (No. 81872733, No. 81872734 and No. 81803353), China Postdoctoral Science Foundation (No. 2020M681792), and the Research & Development Project in Key Areas of Guangdong Province (No. 2019B020203003) to support this study."