Abstract

Background: Aromatase, a cytochrome P450 hemoprotein that is responsible for estrogen biosynthesis by conversion of androgens into estrogens, has been an attractive target in the treatment of hormonedependent breast cancer. Design of new steroidal aromatase inhibitors becomes imperative.

Objective: Synthesis and biological evaluation of two classes of structurally and functionally diverse D-ring pregnenolone pyrazoles as type I aromatase inhibitors and antiproliferative agents.

Methods: Pregnenolone (1) was converted to 3β-hydroxy-21-hydroxymethylidenepregn-5-en-20-one (2), which upon cyclization with phenylhydrazine generated regioisomeric pairs of pyrazoles 4 and 5. Further, Knoevenagel condensation of pregnenolone (1) with 3-oxo-3-phenylpropanenitrile (6) produced 2-benzoyl-3-(3b-hydroxyandrostan- 5-ene-20-ylidene)-but-2-enenitrile (7), which upon cyclization with hydrazine or phenylhydrazine generated the pyrazoles 8 and 9. All new steroidal derivatives were tested for their aromatase inhibition activity using Dibenzylfluorescein (DBF) based fluorescence assay developed by Stresser et al. Antiproliferative activities were measured using Sulforhodamine B assay. The activities were promising and there was a coherence between aromatase inhibitory and antiproliferative activities.

Results: The study reveals the immense potential of pregnenolone pyrazoles as aromatase inhibitors for the treatment of breast cancer. Molecular docking studies proved efficient binding of the new steroidal analogs on human placental aromatase.

Conclusion: In the overall study, most of the compounds exhibited potential activity for the treatment of hormone dependent breast cancer. Compounds 4c and 4d were found to be the most promising pharmacons. Furthermore, compounds 4c and 4d were applied for their molecular docking study on human placental aromatase to predict their possible binding modes with the enzyme. These studies revealed that such molecules have high scope and potential for further investigation towards the treatment of estrogen dependent breast cancer.

Keywords: Aromatase inhibitors, breast cancer, molecular modeling, pharmacons, pregnenolone, pyrazoles.

Graphical Abstract