Syntheses and potential anti-prostate cancer activities of ionone-based chalcones

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Pharmacology

Background:

• Prostate cancer remains a significant health concern, with androgen receptor (AR) signaling driving its progression.
• Developing novel therapeutics targeting AR signaling is crucial for effective treatment.

Purpose of the Study:

• To synthesize and evaluate ionone-based chalcones for anti-proliferative activity against various prostate cancer cell lines.
• To investigate the mechanism of action, specifically the antagonism of wild-type and mutated androgen receptors.

Main Methods:

• Structure-Activity Relationship (SAR) studies were conducted on 43 synthesized ionone-based chalcones.
• In vitro anti-proliferative assays were performed on LNCaP, MDA-PCa-2b, 22Rv1, C4-2B, and PC-3 prostate cancer cell lines.
• The antagonism of DHT-induced transactivation of wild-type and mutated ARs was assessed for potent compounds.

Main Results:

• Several ionone-based chalcones exhibited substantial in vitro anti-proliferative activities.
• Compound 25 demonstrated potent activity with an IC(50) of 0.74 microM in LNCaP cells.
• Compound 25 effectively antagonized DHT-induced transactivation of wild-type and T877A, W741C, H874Y mutated ARs.

Conclusions:

• Ionone-based chalcones represent a promising class of compounds for prostate cancer therapy.
• Compound 25 is identified as a novel chalcone with pan-antagonist activity against androgen receptors, including clinically relevant mutants.