Synthesis of unprecedented steroidal spiro heterocycles as potential antiproliferative drugs

Synthesis of unprecedented steroidal spiro heterocycles as potential antiproliferative drugs 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). http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Medicinal Chemistry Elsevier

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Publisher
Elsevier
Copyright
Copyright © 2017 Elsevier Masson SAS
ISSN
0223-5234
eISSN
1768-3254
D.O.I.
10.1016/j.ejmech.2017.10.063
Publisher site
See Article on Publisher Site

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 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).

Journal

European Journal of Medicinal ChemistryElsevier

Published: Jan 1, 2018

References

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