Design, synthesis and antiproliferative effect of 17β-amide derivatives of 2-methoxyestradiol and their studies on pharmacokinetics

Xiufang Shi; Zhihao Wang; Feng Xu; Xiang Lu; Haifeng Yao; Dandan Wu; Shuaijun Sun; Ruifang Nie; Shuo Gao; Panpan Li; Liwen Xia; Zhenzhong Zhang; Cong Wang

doi:10.1016/j.steroids.2017.09.013

Design, synthesis and antiproliferative effect of 17β-amide derivatives of 2-methoxyestradiol and their studies on pharmacokinetics

Steroids. 2017 Dec:128:6-14. doi: 10.1016/j.steroids.2017.09.013. Epub 2017 Oct 12.

Authors

Xiufang Shi¹, Zhihao Wang¹, Feng Xu¹, Xiang Lu¹, Haifeng Yao², Dandan Wu³, Shuaijun Sun⁴, Ruifang Nie¹, Shuo Gao¹, Panpan Li¹, Liwen Xia¹, Zhenzhong Zhang⁵, Cong Wang⁶

Affiliations

¹ School of Pharmaceutical Sciences, and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, China; Key Laboratory of Henan Province for Drug Quality and Evaluation, China; Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Henan Province, China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, China.
² School of Pharmaceutical Sciences, and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, China; Key Laboratory of Henan Province for Drug Quality and Evaluation, China; Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Henan Province, China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, China; Pharmaceutical Department, The People's Hospital of Chizhou, 3 Baiya Road, Chizhou, Anhui 247000, China.
³ School of Pharmaceutical Sciences, and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, China; Key Laboratory of Henan Province for Drug Quality and Evaluation, China; Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Henan Province, China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, China; Pharmaceutical Department, Affiliated Hospital of Binzhou Medical College, 661 Yellow River 2nd Road, Binzhou, Shandong 256600, China.
⁴ School of Pharmaceutical Sciences, and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, China; Key Laboratory of Henan Province for Drug Quality and Evaluation, China; Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Henan Province, China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, China; Department of Pharmacy, Zhengzhou Central Hospital Affiliated to Zhengzhou University, 195 Tongbai Road, Zhengzhou 450053, Henan, China.
⁵ School of Pharmaceutical Sciences, and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, China; Key Laboratory of Henan Province for Drug Quality and Evaluation, China; Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Henan Province, China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, China. Electronic address: zhangzhenzhong@zzu.edu.cn.
⁶ School of Pharmaceutical Sciences, and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, China; Key Laboratory of Henan Province for Drug Quality and Evaluation, China; Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Henan Province, China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, China. Electronic address: wangcong@zzu.edu.cn.

PMID: 29031938
DOI: 10.1016/j.steroids.2017.09.013

Abstract

A series of 17β-amide-2-methoxyestradiol compounds were synthesized with an aim to enhance the antiproliferative effect of 2-methoxyestradiol. The antiproliferative activity of 2-methoxyestradiol analogs against human cancer cells was investigated. 2-methoxy-3-benzyloxy-17β-chloroacetamide-1,3,5(10)-triene (5e) and 2-methoxy-3-hydroxy-17β-butyramide-1,3,5(10)-triene (6c) had comparable or better antitumor activity than 2-methoxyestradiol. The elimination half-life of 6c (t_1/2β=240.93min) is ten times longer than 2-ME and the area under the curve was seven times (AUC_0-tmin=2068.20±315.74μgmL^-1min) higher than 2-ME, respectively. Whereas 5e had similar pharmacokinetic behavior with 2-ME (t_1/2β=22.28min) with a t_1/2β of 29.5 min. 6c had higher blood concentration, longer actuation duration and better suppression rate against S180 mouse ascites tumor than 2-methoxyestradiol.

Keywords: 2-Methoxyestradiol; Analogs; Antiproliferative effect; Pharmacokinetics.

MeSH terms

2-Methoxyestradiol
Animals
Cell Proliferation / drug effects*
Drug Design
Estradiol / administration & dosage
Estradiol / analogs & derivatives*
Estradiol / chemical synthesis
Estradiol / chemistry
Estradiol / pharmacokinetics
Humans
MCF-7 Cells
Mice
Neoplasms / drug therapy*

Substances

Estradiol
2-Methoxyestradiol