Synthesis and biological evaluation of salpichrolide analogs as antiestrogenic agents

  • Eur J Med Chem. 2014 Jul 23:82:233-41. doi: 10.1016/j.ejmech.2014.05.067.
Juan M Sonego  1 ,  Ezequiel M Rivero  2 ,  Lucía Gargiulo  2 ,  Isabel Lüthy  2 ,  Lautaro D Alvarez  1 ,  Adriana S Veleiro  1 ,  Gerardo Burton  3
Affiliations
  • 1. Departamento de Química Orgánica and UMYMFOR (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EGA Ciudad de Buenos Aires, Argentina.
  • 2. Instituto de Biología y Medicina Experimental - CONICET, Vuelta de Obligado 2490, C1428ADN Ciudad Autónoma de Buenos Aires, Argentina.
  • 3. Departamento de Química Orgánica and UMYMFOR (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EGA Ciudad de Buenos Aires, Argentina. Electronic address: [email protected].
PMID: 24908652 DOI: 10.1016/j.ejmech.2014.05.067
Abstract

The antiestrogenic activity of three natural salpichrolides A, G and B (1, 3 and 4) and of five synthetic analogs containing an aromatic D ring and a simplified side chain (5-9), was evaluated on MCF-7 cells. The 2,3-ene-1-keto Steroids 8 and 9 were obtained from 3β-acetoxy-17(13→18)-abeo-5αH-pregna-13,15,17-trien-20-one, the key step for these syntheses being a Wharton carbonyl rearrangement of a 1,2-epoxy-3-keto steroid to the allylic alcohol using hydrazine hydrate. The antiestrogenic activity was evaluated by performing dose-response experiments in ER(+) MCF-7 breast Cancer cells. Dose-dependent proliferation was quantified via [(3)H]-thymidine incorporation after 3 days treatment. Salpichrolides A, G and B and analogs 5, 8 and 9 were active as antiestrogens with compound 9 being the most active of the synthetic analogs. Compounds 5 and 9 were also evaluated against the ER(-) cell line MDA-MB-231 and shown to be inactive.

Keywords
Antiestrogenic activity; Antiproliferative activity; Salpichrolides; Withanolides.