Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 143, Issue -, Pages 21-32Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2017.10.063
Keywords
Steroids; Oxazoline; Oxazolidine; Heterocycles; Antiproliferative activity
Categories
Funding
- CONACYT-Mexico [240329]
Ask authors/readers for more resources
Herein we report the straightforward preparation of novel conformationally-restricted steroids from trans-androsterone and estrone, decorated with spiranic oxazolidin-2-one or 2-aminooxazoline motifs at C-17 as potential antiproliferative agents. Such unprecedented pharmacophores were accessed using an aminomethylalcohol derivative at C-17 as the key intermediate; reaction of such functionality with triphosgene, or conversion into N-substituted thioureas, followed by an intramolecular cyclodesulfurization reaction promoted by yellow HgO, furnished such spirocycles in excellent yields. Title compounds were tested in vitro against a panel of six human tumor cell lines, named A549 (non small cell lung), HBL-100 (breast), HeLa (cervix), SW1573 (non-small cell lung), T-47D (breast) and WiDr (colon), and the results were compared with steroidal chemotherapeutic agents (abiraterone and galeterone); the A-ring of the steroidal backbone, the nature of the heterocycle and the N-substituents proved to be essential motifs for establishing structure-activity relationships concerning not only the potency but also the selectivity against tumor cell lines. Estrone derivatives, particularly those bearing a spiranic 2-aminooxazoline scaffold were found to be the most active compounds, with Gl(50) values ranging from the low micromolar to the submicromolar level (0.34-1.5 mu M). Noteworthy, the lead compounds showed a remarkable increase in activity against the resistant cancer cell lines (T-47D and WiDr) compared to the anticancer reference drugs (up to 120-fold). (C) 2017 Elsevier Masson SAS. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available