1. Academic Validation
  2. Synthesis of unprecedented steroidal spiro heterocycles as potential antiproliferative drugs

Synthesis of unprecedented steroidal spiro heterocycles as potential antiproliferative drugs

  • Eur J Med Chem. 2018 Jan 1:143:21-32. doi: 10.1016/j.ejmech.2017.10.063.
Laura L Romero-Hernández 1 Penélope Merino-Montiel 2 Socorro Meza-Reyes 1 José Luis Vega-Baez 1 Óscar López 3 José M Padrón 4 Sara Montiel-Smith 5
Affiliations

Affiliations

  • 1 Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Ciudad Universitaria, 72570 Puebla, Pue., Mexico.
  • 2 Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Ciudad Universitaria, 72570 Puebla, Pue., Mexico. Electronic address: penelope.merino@correo.buap.mx.
  • 3 Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, E-41071 Seville, Spain.
  • 4 BioLab, Instituto Universitario de Bio-Orgánica "Antonio González" (IUBO-AG), Centro de Investigaciones Biomédicas de Canarias (CIBICAN), Universidad de La Laguna, c/ Astrofísico Francisco Sánchez 2, 38206 La Laguna, Spain.
  • 5 Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Ciudad Universitaria, 72570 Puebla, Pue., Mexico. Electronic address: maria.montiel@correo.buap.mx.
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).

Keywords

Antiproliferative activity; Heterocycles; Oxazolidine; Oxazoline; Steroids.

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