Synthesis of 2- and 17-substituted estrone analogs and their antiproliferative structure-activity relationships compared to 2-methoxyestradiol.
A novel series of 17-modified and 2,17-modified analogs of 2-methoxyestradiol (2ME2) were synthesized and characterized. These analogs were designed to retain or potentiate the biological activities of 2ME2 and have diminished metabolic liability. The analogs were evaluated for antiproliferative activity against MDA-MB-231 breast tumor cells, antiangiogenic activity in HUVEC, and estrogenic activity on MCF-7 cell proliferation. Several analogs were evaluated for metabolic stability in human liver microsomes and in vivo in a rat cassette dosing model. This study lead to several 17-modified analogs of 2ME2 that have similar or improved antiproliferative and antiangiogenic activity, lack estrogenic properties and have improved metabolic stability compared to 2ME2.
Shah
Jamshed H
JH
EntreMed, Inc., 9640 Medical Center Drive, Rockville, MD 20850, USA.
Agoston
Gregory E
GE
Suwandi
Lita
L
Hunsucker
Kimberly
K
Pribluda
Victor
V
Zhan
Xiaoguo H
XH
Swartz
Glenn M
GM
LaVallee
Theresa M
TM
Treston
Anthony M
AM
D000077584:2-Methoxyestradiol; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004970:Estrone / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051381:Rats; D013329:Structure-Activity Relationship
D004970:Estrone; D004958:Estradiol; D000077584:2-Methoxyestradiol