title: 8-alkylthio-6-thio-substituted theophylline analogues as selective noncompetitive progesterone receptor antagonists.
abstract: The progesterone receptor (PR) plays a key role in reproduction and is important in cancers of the reproductive tract. Current PR antagonists usually compete for progestin binding in the PR ligand-binding pocket and often exhibit cross-binding with other members of the steroid receptor family. Using stably transfected cells expressing reporter genes, a set of ∼150 theophylline analogues were screened for their ability to inhibit progesterone, estrogen, glucocorticoid and androgen signaling. The structure-activity studies presented here identify branched 8-alkylthio-6-thio-substitutions of theophylline as selective PR inhibitors. 6-Thio-8-(2-ethylbutyl)thiotheophylline (51), the most extensively studied derivative, does not act by competing with progestins for binding in the ligand-binding pocket of PR. It demonstrated the ability to inhibit the mouse mammary tumor virus (MMTV)-luciferase reporter and endogenous PR-regulated alkaline phosphatase activity in T47D breast cancer cells. Compound 51 is the lead member of a novel class of PR inhibitors that act outside the PR ligand-binding pocket, thus serving as a novel probe to investigate PR action and a lead for further development.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Irene O
authors.initials: IO
authors.lastname: Aninye
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Berg
authors.forename: Andy R
authors.initials: AR
authors.lastname: Mollo
authors.forename: Steven K
authors.initials: SK
authors.lastname: Nordeen
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Wilson
authors.forename: David J
authors.initials: DJ
authors.lastname: Shapiro
mesh_terms: D002460:Cell Line; D006801:Humans; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013379:Substrate Specificity; D013455:Sulfur / Q000737:chemistry*; D013806:Theophylline / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D011980:Receptors, Progesterone; D013455:Sulfur; D013806:Theophylline