Pregnenolone derivatives as potential anticancer agents

Pregnenolone (1) was used as a template to develop new anticancer compounds. Ring-D modification of 1 resulted in the synthesis of benzylidenes 2–17, pyrazolines 18–76, pyrazoles 85–91, hydrazones 77–84, and oximes 92–107 derivatives. The structure of compound 107 was also deduced through single crystal X-ray diffraction studies. The inclusion of furanyl and pyridyl rings to pregnenolone skeleton increases the cytotoxicity of all compounds significantly. Among benzylidene derivatives, only heterocyclic enone 8 (IC50 = 0.74 μM/mL against HepG2), and 17 (IC50 = 4.49 μM/mL against HepG2, IC50 = 5.01 μM/mL against MDA-MB-230 cancer cell line) exhibited a significant activity. The cytotoxicity data of pyrazoline derivatives 18–76 revealed that only furanyl bearing pyrazolines 40, 42–44, 48, and 49 exhibited significant activities. While all (O-carboxymethyl) oximes, hydazones, and pyrazoles derivatives of pregnenolone did not show any significant activity against both the cell lines. Thus the furanyl bearing enone 8 (IC50 = 0.74 μM/mL against HepG2), and its pyrazoline derivative 48 (IC50 = 0.91 μM/mL against MDA-MB-230 cancer cell lines) were identified as the most active compounds in all derivatives of pregnenolone.

A new series of pregnenolone derivatives was synthesized by parallel synthesis. Their anticancer activity against cancer cell lines was evaluated and SAR established.Figure optionsDownload as PowerPoint slideHighlights
► The synthesis of a series of pregnenolone derivatives 2–107 has been described which were evaluated for their cytotoxicity against HepG2 and MDA-MB-231 cell lines.
► Among all derivatives, the heterocyclic enone 8 (IC50 = 0.74 μM/mL against HepG2), its pyrazoline derivative 48 (IC50 = 0.91 μM/mL against MDA-MB-230 cancer cell lines) were identified as the most active compounds.
► All (O-carboxymethyl) oxime, hydazones and pyrazoles derivatives of pregnenolone were found to be inactive against both the cancer cell lines.