New biaryl-chalcone derivatives of pregnenolone via Suzuki–Miyaura cross-coupling reaction. Synthesis, CYP17 hydroxylase inhibition activity, QSAR, and molecular docking study

• The synthesis of substituted biaryl chalcone steroids via Suzuki–Miyaura cross-coupling reaction was reported.
• The trans-configuration of the chalconyl steroid analogs were assigned.
• Inhibition activity of CYP17 hydroxylase enzyme was studied.
• Molecular modeling study of the active steroid with the amino acids of CYP17 hydroxylase was performed.

A new class of steroids is being synthesized for its ability to prevent intratumoral androgen production by inhibiting the activity of CYP17 hydroxylase enzyme. The scheme involved the synthesis of chalcone derivative of pregnenolone 5 which was further modified to the corresponding biaryl-chalcone pregnenolone analogs 16–25 using Suzuki–Miyaura cross-coupling reaction. The synthesized compounds were tested for activity using human CYP17α hydroxylase expressed in Escherichia coli. Compounds 21 was the most active inhibitor in this series, with IC50 values of 0.61 μM and selectivity profile of 88.7% inhibition of hydroxylase enzyme. Molecular docking study of 21 was performed and showed the hydrogen bonds and hydrophobic interaction with the amino acid residues of the active site of CYP17.

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