Design, Synthesis, and Biological Evaluation of Heterocyclic-Fused Pyrimidine Chemotypes Guided by X-ray Crystal Structure with Potential Antitumor and Anti-multidrug Resistance Efficacy Targeting the Colchicine Binding Site
机构:[1]Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital and Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, China四川大学华西医院[2]Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212 Sichuan, China[3]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, China四川大学华西医院[4]Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital and Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, China四川大学华西医院[5]Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212 Sichuan, China[6]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, China四川大学华西医院[7]Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital and Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, China四川大学华西医院[8]Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212 Sichuan, China[9]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, China四川大学华西医院[10]Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, China四川大学华西医院[11]Department of Pharmacy, Western Theater Command Hospital, Chengdu 610083 Sichuan, China[12]Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, China四川大学华西医院[13]Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212 Sichuan, China[14]State Key Laboratory of Biotherapyand Cancer Center, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, China四川大学华西医院[15]Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, China四川大学华西医院[16]Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212 Sichuan, China[17]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, China四川大学华西医院[18]Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, China四川大学华西医院[19]Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212 Sichuan, China[20]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, China四川大学华西医院[21]Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, China四川大学华西医院[22]Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212 Sichuan, China[23]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, China四川大学华西医院[24]Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital and PrecisionMedicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, China四川大学华西医院[25]Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212 Sichuan, China[26]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, China四川大学华西医院
Herein, a series of quinazoline and heterocyclic fused pyrimidine analogues were designed and synthesized based on the X-ray co-crystal structure of lead compound 3a, showing efficacious antitumor activities. Two analogues, 15 and 27a, exhibited favorable antiproliferative activities, which were more potent than lead compound 3a by 10-fold in MCF-7 cells. In addition, 15 and 27a exhibited potent antitumor efficacy and tubulin polymerization inhibition in vitro. 15 reduced the average tumor volume by 80.30% (2 mg/kg) in the MCF-7 xenograft model and 75.36% (4 mg/kg) in the A2780/T xenograft model, respectively. Most importantly, supported by structural optimization and Mulliken charge calculation, X-ray co-crystal structures of compounds 15, 27a, and 27b in complex with tubulin were resolved. In summary, our research provided the rational design strategy of colchicine binding site inhibitors (CBSIs) based on X-ray crystallography with antiproliferation, antiangiogenesis, and anti-multidrug resistance properties.
基金:
This work was supported by the National Natural Science
Foundation of China (82073318, 81903502), Ministry of
Science and Technology of China (2022YFC2303700), and
Natural Science Foundation of Sichuan Province
(2022NSFSC1365). In addition, we thank Dr. Linxi Wan
(Sichuan University) for testing HRMS(ESI)+ and NMR. We
thank Yiran Tao (West China-California Research Center for
Predictive Intervention Medicine, West China Hospital,
Sichuan University) for FACS data acquisition.
语种:
外文
PubmedID:
中科院(CAS)分区:
出版当年[2023]版:
大类|1 区医学
小类|1 区药物化学
最新[2023]版:
大类|1 区医学
小类|1 区药物化学
第一作者:
第一作者机构:[1]Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital and Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, China[2]Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212 Sichuan, China[3]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, China
共同第一作者:
通讯作者:
通讯机构:[24]Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital and PrecisionMedicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, China[25]Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212 Sichuan, China[26]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, China
推荐引用方式(GB/T 7714):
Tan Lun,Wu Chengyong,Zhang Jifa,et al.Design, Synthesis, and Biological Evaluation of Heterocyclic-Fused Pyrimidine Chemotypes Guided by X-ray Crystal Structure with Potential Antitumor and Anti-multidrug Resistance Efficacy Targeting the Colchicine Binding Site[J].Journal of medicinal chemistry.2023,doi:10.1021/acs.jmedchem.2c02115.
APA:
Tan Lun,Wu Chengyong,Zhang Jifa,Yu Quanwei,Wang Xiye...&Wang Yuxi.(2023).Design, Synthesis, and Biological Evaluation of Heterocyclic-Fused Pyrimidine Chemotypes Guided by X-ray Crystal Structure with Potential Antitumor and Anti-multidrug Resistance Efficacy Targeting the Colchicine Binding Site.Journal of medicinal chemistry,,
MLA:
Tan Lun,et al."Design, Synthesis, and Biological Evaluation of Heterocyclic-Fused Pyrimidine Chemotypes Guided by X-ray Crystal Structure with Potential Antitumor and Anti-multidrug Resistance Efficacy Targeting the Colchicine Binding Site".Journal of medicinal chemistry .(2023)