Synthesis, bioactivity, and molecular docking studies: novel arylpiperazine derivatives as potential new-resistant AR...

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Androgen deprivation therapy (ADT) is standard for prostate cancer (PCa), but resistance develops, leading to castration-resistant PCa (CRPC).
• CRPC is characterized by uncontrolled tumor growth and treatment failure due to evolving androgen sensitivity.
• Novel therapeutic strategies are crucial to overcome ADT resistance in prostate cancer.

Purpose of the Study:

• To identify novel androgen receptor (AR) antagonists for potential prostate cancer therapy.
• To synthesize and evaluate ether-type arylpiperazine derivatives for antiproliferative activity.
• To investigate the structure-activity relationships (SAR) and binding affinities of these compounds.

Main Methods:

• Synthesis of novel ether-type arylpiperazine derivatives.
• In vitro cytotoxicity assays against cancer cell lines.
• Androgen receptor binding affinity and antagonistic activity assays.
• Molecular docking studies to predict binding interactions.

Main Results:

• Several derivatives exhibited potent antiproliferative effects on cancer cells.
• Compounds 17, 19, 20, and 23 demonstrated significant AR antagonistic activity (>60% inhibition) and strong AR binding.
• Compound 19 showed specific binding to the AR ligand-binding pocket via Van der Waals interactions.

Conclusions:

• Novel arylpiperazine derivatives show promise as potent AR antagonists.
• Compounds 17, 19, 20, and 23 are lead candidates for developing new prostate cancer therapeutics.
• This research offers a promising direction for novel anticancer agents targeting AR in prostate cancer therapy.