title: Synthesis and antiprogestational properties of novel 17-fluorinated steroids.
abstract: Progesterone receptor (PR) plays a key role in reproductive functions, and compounds that inhibit progesterone action (antiprogestins) have potential use in the treatment of estrogen- and progesterone-dependent diseases, including uterine leiomyomas and breast cancer. In the present study, we chemically synthesized novel 17-fluorinated steroids and evaluated the cytotoxicity profiles of these compounds in T47D breast cancer cells compared to the activity of known antiprogestins, including ZK230 211, RU-486, CDB2914, CDB4124 and ORG33628. We analyzed in vitro receptor-binding assays and PR-transactivation assays to establish the antiprogestational activity of these molecules. The representative antiprogestin EC304 was found to inhibit in vitro tumorigenicity in a dose-dependent fashion in T47D cells by a colony formation assay at 1 and 10nM concentrations. The potent in vivo antiprogestational activity of EC304 was also demonstrated in an antinidation assay for the interruption of early pregnancy in rats. The strong antiprogestational activity and absence of antiglucocorticoid activity in EC compounds may demonstrate their utility in the treatment of leiomyoma, endometriosis and breast cancer.
authors.affiliation: Evestra, Inc., San Antonio, TX, USA. knickisch@evestra.com
authors.forename: Klaus
authors.initials: K
authors.lastname: Nickisch
authors.forename: Hareesh B
authors.initials: HB
authors.lastname: Nair
authors.forename: Narkunan
authors.initials: N
authors.lastname: Kesavaram
authors.forename: Baishakhi
authors.initials: B
authors.lastname: Das
authors.forename: Robert
authors.initials: R
authors.lastname: Garfield
authors.forename: Shao-Qing
authors.initials: SQ
authors.lastname: Shi
authors.forename: Shylesh S
authors.initials: SS
authors.lastname: Bhaskaran
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Grimm
authors.forename: Dean P
authors.initials: DP
authors.lastname: Edwards
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D010064:Embryo Implantation / Q000187:drug effects; D004963:Estrenes / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D054879:Halogenation; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D010766:Phosphorylation; D011247:Pregnancy; D011499:Protein Processing, Post-Translational; D051381:Rats; D017207:Rats, Sprague-Dawley; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004963:Estrenes; D006845:Hydrocarbons, Fluorinated; D011980:Receptors, Progesterone
keywords: Antiprogestin; Breast cancer; Fluorine; GR; MEM; PR; glucocorticoid receptor; minimal essential medium; progesterone receptor