Article
Synthesis of unprecedented steroidal spiro heterocycles as potential antiproliferative drugs
Author/s | Romero Hernández, Laura L.
Merino Montiel, Penélope Meza Reyes, Socorro Vega Baez, José Luis López López, Óscar Padrón, José M. Montiel Smith, Sara |
Department | Universidad de Sevilla. Departamento de Química orgánica |
Publication Date | 2018-01-01 |
Deposit Date | 2024-02-06 |
Published in |
|
Abstract | 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 ... 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 GI50 values ranging from the low micromolar to the submicromolar level (0.34–1.5 μM). 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). |
Funding agencies | CONACYT-México |
Project ID. | 240329 |
Citation | Romero Hernández, L.L., Merino Montiel, P., Meza Reyes, S., Vega Baez, J.L., López López, Ó., Padrón, J.M. y Montiel Smith, S. (2018). Synthesis of unprecedented steroidal spiro heterocycles as potential antiproliferative drugs. European Journal of Medicinal Chemistry, 143, 21-32. https://doi.org/10.1016/j.ejmech.2017.10.063. |
Files | Size | Format | View | Description |
---|---|---|---|---|
Synthesis of unprecedented_C.pdf | 1.928Mb | [PDF] | View/ | Versión aceptada |