Exploring the binding dynamics of triazolyl-thio-oxazines for MDM2-p53 disruption: Design, synthesis, and p53...

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Computational Chemistry

Background:

• The mouse double minute 2 homolog (MDM2)-p53 interaction is crucial in cancer, as MDM2 inactivates the tumor suppressor p53.
• Inhibiting the MDM2-p53 interaction is a validated strategy for cancer therapy.

Purpose of the Study:

• To design and synthesize novel compounds targeting the MDM2-p53 interaction based on a three-finger pharmacophore model.
• To evaluate the binding affinity, stability, pharmacokinetic properties, and anticancer efficacy of the designed compounds.

Main Methods:

• Rational drug design using a three-finger pharmacophore model.
• Synthesis and characterization of four triazolyl-thio-oxazines (4a-d) using NMR, IR, mass spectrometry, and X-ray crystallography (for 4a).
• In silico studies including molecular dynamics simulations and MM-GBSA analysis.
• In vitro cytotoxicity assays (MCF-7 cells) and western blot analysis to assess p53 and p21 upregulation.

Main Results:

• All synthesized compounds (4a-d) bound to the MDM2 binding site with high affinity.
• Compound 4a exhibited superior binding stability and a favorable MM-GBSA binding score compared to Nutlin-3a and p53 peptide.
• Compound 4a demonstrated potent cytotoxicity against MCF-7 breast cancer cells (IC50 = 4.379 μM) and significantly upregulated p53 and p21.
• Differential effects on p53/p21 levels in different cell lines confirmed wild-type p53 upregulation.

Conclusions:

• The designed triazolyl-thio-oxazines effectively inhibit the MDM2-p53 interaction.
• Compound 4a shows significant promise as an MDM2-p53 interaction inhibitor with favorable drug-like properties.
• Further biological evaluation of compound 4a is warranted for its potential as a cancer therapeutic.