Synthesis and evaluation of modified chalcone based p53 stabilizing agents

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Cancer Biology

Background:

• The tumor suppressor protein p53 is crucial in preventing cancer by inducing cell cycle arrest and apoptosis.
• Activating wild-type p53 using small molecules is a promising strategy for cancer treatment.

Purpose of the Study:

• To synthesize and evaluate a series of novel chalcone derivatives for their antiproliferative activity and ability to stabilize p53.
• To explore the structure-activity relationship of these chalcones in cancer cells.

Main Methods:

• Nineteen chalcone derivatives were synthesized via Claisen-Schmidt condensation and characterized using spectroscopic methods (NMR, HRMS, IR) and melting point analysis.
• Antiproliferative activity was assessed against human colorectal (HCT116) and breast (CAL-51) cancer cell lines, determining GI50 values.
• p53 stabilization was evaluated by Western blot analysis in the presence and absence of cycloheximide (CHX).

Main Results:

• Nine chalcone compounds exhibited potent antiproliferative activity, with GI50 values in the low micromolar to submicromolar range.
• Specific compounds, (E)-3-(4-chlorophenyl)-1-phenylprop-2-en-1-one and (E)-3-(4-methoxyphenyl)-1-phenylprop-2-en-1-one, rapidly accumulated p53 in HCT116 cells.
• p53 stabilization was confirmed to be regulated at the post-translational level by inhibiting protein degradation, and the conjugated ketone moiety was essential for activity.

Conclusions:

• The synthesized chalcones demonstrate significant potential as anticancer agents by stabilizing the p53 protein.
• These compounds serve as valuable fragment leads for developing more potent p53-stabilizing drugs with enhanced anti-proliferative effects.