There is much interest in the use of phytoestrogens such as coumestrol in breast cancer intervention due to their antiestrogenic activity and multiple modes of tumor cell death. However, the clear beneficial effects of naturally occurring estrogen mimetic coumestrol remain controversial due to experimental evidence that it has been shown to stimulate MCF-7 cell proliferation via agonist effect on estrogen receptor at low concentration. Herein, to disconnect the ER interaction and apoptosis-specific mechanism of coumestrol, various 3, 9-di-O-substituted coumestrols (7a-7e) and their furan ring-opened analogs (5a-5e) were synthesized and assessed for antiproliferative properties. Attachment of a dimethylamine-containing side chain to 3-O of coumestrol led to the most promising compound 7e with improved antiproliferative activity (1.7-fold increase) against MCF-7 cells, decreased estrogen activity ( > 20 times weaker ERa binder) and a novel action to induce apoptosis. Mechanistic studies revealed that 7e is a tubulin polymerization inhibitor, which could arrest cell cycle at G2/M phase and induce apoptosis along with the decrease of mitochondrial membrane potential. In summary, such subtle modifications to the 3, 9-di-hydroxyl groups of coumestrol allow the generation of a novel apoptosis inducer with distinct pharmacological properties, providing an excellent starting point to future development of novel tumor-vascular disrupting agents targeting tubulin.
[1]China Pharmaceut Univ, Jiangsu Key Lab Drug Design & Optimizat, State Key Lab Nat Med, Nanjing 210009, Jiangsu, Peoples R China;
[2]China Pharmaceut Univ, Sch Pharm, Dept Med Chem, Nanjing 210009, Jiangsu, Peoples R China;
[3]Fudan Univ, Minist Educ, Key Lab Smart Drug Delivery, Sch Pharm, Lane 826,Zhangheng Rd, Shanghai 201203, Peoples R China;
[4]Xian Med Univ, Shaanxi Key Lab Brain Disorders, Xian 710021, Shaanxi, Peoples R China;
[5]Xian Med Univ, Inst Basic & Translat Med, Xian 710021, Shaanxi, Peoples R China
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