Structural Optimization of Isoquinoline Derivatives from Lycobetaine and Their Inhibitory Activity against...

Area of Science:

• Medicinal Chemistry
• Oncology
• Pharmacology

Background:

• Neuroendocrine prostate cancer (NEPC) is an aggressive malignancy with poor prognosis and limited treatment options.
• The natural product lycobetaine has demonstrated antitumor properties, prompting investigation into its derivatives.
• Existing therapies for NEPC are often ineffective due to hormone resistance.

Purpose of the Study:

• To synthesize and evaluate novel isoquinoline derivatives based on the lycobetaine scaffold for NEPC treatment.
• To identify a potent and selective inhibitor of NEPC cell proliferation.
• To elucidate the mechanism of action of the most promising compound.

Main Methods:

• Simplified the lycobetaine scaffold to create compound 1, an isoquinoline derivative.
• Conducted structure-activity relationship (SAR) studies to optimize compound 1, leading to compound 46.
• Assessed antiproliferative activity against the NEPC cell line LASCPC-01 and prostate cancer cell line PC-3.
• Performed cell-based assays to investigate cell cycle arrest, apoptosis, and neuroendocrine marker expression.

Main Results:

• Compound 46 exhibited potent inhibition of LASCPC-01 cells with an IC50 of 0.47 μM.
• Compound 46 demonstrated significant selectivity for NEPC over PC-3 cells (selectivity index > 190-fold).
• Both compound 46 and lycobetaine induced G1 cell cycle arrest and apoptosis dose-dependently.
• Compound 46 slightly upregulated neuroendocrine markers, unlike lycobetaine, suggesting a distinct mechanism.

Conclusions:

• Compound 46 is a potent and selective inhibitor of neuroendocrine prostate cancer cell growth.
• The compound induces cell cycle arrest and apoptosis, representing a promising therapeutic candidate.
• Compound 46 may exert its antitumor effects via a mechanism distinct from lycobetaine, requiring further investigation.