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

摘要

Graphical abstract Display Omitted Highlights ? First reported 17β-amide derivatives of 2-methoxyestradiol. ? The single crystal X-ray diffraction confirmed the configuration of 17β-butyrylamino of 6c . ? Three derivatives had similar or even better effects than 2-ME in antiproliferative assay. ? Pharmacokinetic tests showed that the half-life of 6c was ten times that of 2ME. 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 ?1 min) 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.