8-Alkylthio-6-thio-substituted theophylline analogues as selective noncompetitive progesterone receptor antagonists Public Deposited
- Creator
- Aninye, Irene O.
- Berg, Kenneth C.
- Mollo, Andy R.
- Nordeen, Steven K.
- Wilson, Elizabeth M.
- Shapiro, David J.
- 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.
- Date of publication
- 2012
- Keyword
- Phosphodiesterase 4 inhibitor
- Antiprogestérone
- Sex steroid hormone
- Phosphodiesterase inhibitor
- Théophylline
- Progesterone
- Progestagen
- Stéroïde
- Récepteur progestérone
- Relation structure activité
- Structure activity relationship
- Antiprogesterone
- Progesterone receptor
- Progestérone
- Ovarian hormone
- Steroid
- Theophylline analogue
- Récepteur biologique
- Small molecule inhibitor
- Biological receptor
- Theophylline
- Structure activity relation
- Xanthine derivatives
- Steroid receptor
- DOI
- Identifier
- Publisher DOI: https://doi.org/10.1016/j.steroids.2012.02.003
- PMID: 22421057
- PMCID: PMC3384716
- Onescience id: 7423bdbf51f0a69808731584fe9135827f9c2b0e
- Resource type
- Article
- Rights statement
- In Copyright
- Journal title
- Steroids
- Journal volume
- 77
- Journal issue
- 6
- Page start
- 596
- Page end
- 601
- Language
- English
- ISSN
- 0039-128X
- 1878-5867
- Parents:
This work has no parents.
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