Design, synthesis and evaluation of novel enzalutamide analogues as potential anticancer agents

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Pharmacology

Background:

• Enzalutamide is an androgen receptor (AR) inhibitor effective against castration-resistant prostate cancer (CRPC).
• AR mutation (F876L) confers resistance by converting Enzalutamide from an antagonist to an agonist.
• Developing novel analogues is crucial to overcome Enzalutamide resistance mechanisms in CRPC.

Purpose of the Study:

• To design and synthesize novel Enzalutamide analogues to overcome AR-mediated resistance.
• To evaluate the in vitro antiproliferative activity of synthesized compounds against prostate cancer cell lines.
• To investigate the binding mechanism of potential AR inhibitors using computational methods.

Main Methods:

• Designed Enzalutamide derivatives based on shape and electrostatic pharmacophoric features for AR binding.
• Synthesized ten novel derivatives, including compounds 6a-j.
• Evaluated in vitro antiproliferative activity on DU-145, LNCaP, and PC3 prostate cancer cell lines.
• Performed molecular docking, molecular dynamics simulations, and MM-GBSA calculations to study binding mechanisms.

Main Results:

• Two novel compounds, 6c and 6h, exhibited promising in vitro antiproliferative activity against prostate cancer cell lines (IC50: 18.26 to 20.31 μM).
• Computational studies (docking, MD, MM-GBSA) supported the in vitro findings, elucidating the binding mechanism.
• The results provide strong theoretical support for the designed analogues as potential AR inhibitors.

Conclusions:

• Novel Enzalutamide analogues were successfully designed and synthesized to combat AR-mediated resistance.
• Compounds 6c and 6h demonstrate significant potential for treating Enzalutamide-resistant prostate cancer.
• The study provides a strong theoretical foundation for further development of these analogues.