title: Synthesis of 2- and 17-substituted estrone analogs and their antiproliferative structure-activity relationships compared to 2-methoxyestradiol.
abstract: 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.
authors.affiliation: EntreMed, Inc., 9640 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Jamshed H
authors.initials: JH
authors.lastname: Shah
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Agoston
authors.forename: Lita
authors.initials: L
authors.lastname: Suwandi
authors.forename: Kimberly
authors.initials: K
authors.lastname: Hunsucker
authors.forename: Victor
authors.initials: V
authors.lastname: Pribluda
authors.forename: Xiaoguo H
authors.initials: XH
authors.lastname: Zhan
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Swartz
authors.forename: Theresa M
authors.initials: TM
authors.lastname: LaVallee
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Treston
mesh_terms: 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
chemical_list: D004970:Estrone; D004958:Estradiol; D000077584:2-Methoxyestradiol