Fluorescent p53 helix mimetics pairing anticancer and bioimaging properties

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Cancer Therapeutics

Background:

• Targeting the p53-HDM2 protein complex is a key strategy for cancer therapy, aiming to restore p53-mediated apoptosis.
• Existing p53 helix mimetics lack inherent fluorescence and demonstrated cell permeability for combined therapeutic and imaging applications.
• Developing intrinsically fluorescent and biocompatible molecules is crucial for theranostic applications in cancer research.

Purpose of the Study:

• To design and synthesize novel, inherently fluorescent, and cell-permeable helix mimetics for theranostic cancer applications.
• To evaluate the therapeutic potential and bioimaging capabilities of these novel molecules in cancer models.
• To investigate the cellular uptake, distribution, and mechanism of action of these fluorescent helix mimetics.

Main Methods:

• Synthesis of novel phthalimide-based helix mimetics incorporating p53 'hotspot' mimicking residues.
• Conformational analysis and molecular docking studies to predict molecular interactions.
• In vitro cytotoxicity assays against human cancer cell lines (U87MG, A549, MDA-MB-231) and a non-cancerous cell line (HEK293).
• Fluorescence microscopy to assess cellular uptake, distribution, and localization.

Main Results:

• Successfully synthesized intrinsically fluorescent helix mimetics with a solvatochromic phthalimide core.
• Demonstrated anticancer activity in the micromolar range across tested cancer cell lines.
• Utilized fluorescence properties to visualize cellular permeability, distribution, and selectivity towards cancer cells.

Conclusions:

• The developed theranostic helix mimetics offer a dual approach for cancer treatment and real-time bioimaging.
• These molecules show promise as a new class of anticancer agents with built-in imaging capabilities.
• The fluorescence provides critical insights into the pharmacokinetics and pharmacodynamics of these novel therapeutic candidates.