Profiling crystal engineered ligands for targeting treatment resistant androgen receptors

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Crystal Engineering

Background:

• Prostate cancer (PCa) significantly impacts aging males, often progressing to castration-resistant prostate cancer (CRPC).
• Current treatments for CRPC lack long-term efficacy, necessitating novel therapeutic agents.
• Dysregulation of androgen receptor (AR) signaling is central to PCa development and progression.

Purpose of the Study:

• To develop novel tetra-aryl cyclobutanes (CBs) as potential therapeutics for CRPC.
• To explore the application of crystal engineering and solid-state synthesis for generating CBs.
• To investigate the structure-function relationships and therapeutic potential of CBs against AR-mediated pathways in CRPC.

Main Methods:

• Utilized crystal engineering principles for solid-state synthesis of CBs via [2+2] photodimerization.
• Employed derivatization strategies to expand the class of CBs.
• Conducted in vitro assays to assess AR transcriptional activity, receptor translocation, and cell viability.
• Performed molecular docking to identify binding interactions and ligand-binding potential within CB/AR complexes.

Main Results:

• Achieved quantitative and purification-free synthesis of CBs using solid-state reactions.
• Demonstrated that CBs modulate AR-mediated transcriptional activity and receptor translocation.
• Identified potential binding interactions between CBs and the AR, suggesting a novel mechanism of action.
• Showcased the therapeutic potential of CBs against CRPC cell viability in vitro.

Conclusions:

• Tetra-aryl cyclobutanes (CBs) represent a promising class of compounds for treating castration-resistant prostate cancer (CRPC).
• Green chemistry and crystal engineering provide an efficient and sustainable route for synthesizing novel CB drug candidates.
• Further research into CBs could lead to effective pharmacological interventions for advanced prostate cancer.