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Synthesis of unprecedented steroidal spiro heterocycles as potential antiproliferative drugs.

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_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Romero-Hernández LL,Merino-Montiel P,Meza-Reyes S,Vega-Baez JL,López Ó,Padrón JM,Montiel-Smith S

doi

10.1016/j.ejmech.2017.10.063

subject

Has Abstract

pub_date

2018-01-01 00:00:00

pages

21-32

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(17)30865-6

journal_volume

143

pub_type

杂志文章

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