Design and synthesis of 4-benzyl-1-(2H)-phthalazinone derivatives as novel androgen receptor antagonists

• A series of 4-benzyl-1-(2H)-phthalazinone derivatives were synthesized.
• 4-Benzyl-1-(2H)-phthalazinone with ortho-substituent was a novel scaffold of AR antagonist.
• Compound 11c exhibited potent AR antagonistic activity towards both wt and T877A-mutated ARs.
• Docking simulation suggested the AR binding feature and mechanism of AR antagonism of 11c.

The androgen receptor (AR) plays important roles in multiple physiological functions, including differentiation, growth, and maintenance of male reproductive organs, and also has effects on hair and skin. In this paper, we report the synthesis of nonsteroidal AR antagonists having a 4-benzyl-1-(2H)-phthalazinone skeleton. Among the synthesized compounds, 11c with two ortho-substituents on the phenyl group potently inhibited SC-3 cell proliferation (IC50: 0.18 μM) and showed high wt AR-binding affinity (IC50: 10.9 μM), comparable to that of hydroxyflutamide (3). Compound 11c also inhibited proliferation of LNCaP cells containing T877A-mutated AR. Docking study of 11c with the AR ligand-binding domain indicated that the benzyl group is important for the antagonism. These phthalazinone derivatives may be useful for investigating potential clinical applications of AR antagonists.

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