Secosteroid - 1,3,4-Oxadiazole Hybrids: Synthesis and Evaluation of Their Activity Against Hormone-Dependent Breast Cancer Cells.

Abstract

This study focused on the synthesis of secosteroids with good antiproliferative properties against hormone-dependent breast cancer. A straightforward and efficient method for synthesizing secosteroid - 1,3,4-oxadiazole hybrids was developed starting from 13α-hydroxy-3-methoxy-13,17-secoestra-1,3,5(10)-trien-17-oic acid hydrazide. The cyclization of hydrazide moiety with CS₂ into 1,3,4-oxadiazole-2(3H)-thione fragment followed by sulfur alkylation resulted in the formation of various secosteroid - 2-mercapto-1,3,4-oxadiazole hybrids. These novel compounds were evaluated for their antiproliferative activity against the hormone-dependent human breast cancer cell line MCF-7. Among the synthesized hybrids, compounds 3i, 3o, and 3q displayed notable antiproliferative effects, with IC₅₀ values ranging from 6.5 to 8.9µM, comparable to the reference drug cisplatin. Furthermore, compound 3i showed minimal toxicity toward non-cancerous hFB-hTERT fibroblasts, indicating high selectivity. Compounds 3o and 3q exhibited antiestrogenic activity. Additionally, their effects on PARP and Bcl-2 suggest a pro-apoptotic mechanism of action. These findings highlight the potential of secosteroidal hybrids as promising candidates for the development of new anti-breast cancer agents targeting ERα and apoptosis pathways.