Synthesis and Biological Evaluation of Salpichrolide Analogues as Antiestrogenic Agents

JUAN M. SONEGO; EZEQUIEL M. RIVERO; LUCIA GARGIULO; ISABEL LÜTHY; LAUTARO D. ÁLVAREZ; ADRIANA S. VELEIRO; GERARDO BURTON

EUROPEAN JOURNAL OF MEDICAL CHEMISTRY

ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER

Año: 2014 vol. 82 p. 233 - 241

0223-5234

The antiestrogenic activity of three natural salpichrolides A, G and B (1, 3 and 4) and of five synthetic analogues 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 3b-acetoxy-17(13-18)-abeo-5aH-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 [3H]-thymidine incorporation after 3 days treatment. Salpichrolides A, G and B and analogues 5, 8 and 9 were active as antiestrogens with compound 9 being the most active of the synthetic analogues. Compounds 5 and 9 were also evaluated against the ER(-) cell line MDA-MB-231 and shown to be inactive.