Effects of 7-O substitutions on estrogenic and anti-estrogenic activities of daidzein analogues in MCF-7 breast cancer cells.
Daidzein (1) is a natural estrogenic isoflavone. We report here that 1 can be transformed into anti-estrogenic ligands by simple alkyl substitutions of the 7-hydroxyl hydrogen. To test the effect of such structural modifications on the hormonal activities of the resulting compounds, a series of daidzein analogues have been designed and synthesized. When MCF-7 cells were treated with the analogues, those resulting from hydrogen substitution by isopropyl (3d), isobutyl (3f), cyclopentyl (3g), and pyrano- (2) inhibited cell proliferation, estrogen-induced transcriptional activity, and estrogen receptor (ER) regulated progesterone receptor (PgR) gene expression. However, methyl (3a) and ethyl (3b) substitutions of the hydroxyl proton only led to moderate reduction of the estrogenic activities. These results demonstrated the structural requirements for the transformation of daidzein from an ER agonist to an antagonist. The most effective analogue, 2, was found to reduce in vivo estrogen stimulated MCF-7 cell tumorigenesis using a xenograft mouse model.
Jiang
Quan
Q
Department of Chemistry, Xavier University of Louisiana, New Orleans, Louisiana 70125, USA.
Payton-Stewart
Florastina
F
Elliott
Steven
S
Driver
Jennifer
J
Rhodes
Lyndsay V
LV
Zhang
Qiang
Q
Zheng
Shilong
S
Bhatnagar
Deepak
D
Boue
Stephen M
SM
Collins-Burow
Bridgette M
BM
Sridhar
Jayalakshmi
J
Stevens
Cheryl
C
McLachlan
John A
JA
Wiese
Thomas E
TE
Burow
Matthew E
ME
Wang
Guangdi
G
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000037:antagonists & inhibitors; D004967:Estrogens / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007529:Isoflavones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D011980:Receptors, Progesterone / Q000096:biosynthesis; D020218:Response Elements; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic; D023041:Xenograft Model Antitumor Assays
C552105:3-(4-hydroxyphenyl)-8,8-dimethyl-8H-pyrano(2,3-f)chromen-4-one; D000970:Antineoplastic Agents; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D004967:Estrogens; D007529:Isoflavones; D011980:Receptors, Progesterone; D004958:Estradiol; C004742:daidzein