Visualization of Modified Bisarylbutadiyne-Tagged Small Molecules in Live-Cell Nuclei by Stimulated Raman Scattering...

Area of Science:

• Chemical Biology
• Molecular Imaging
• Drug Discovery

Background:

• Visualizing small-molecule drugs in living cells is crucial for developing effective and safe therapeutics.
• Current methods like fluorescence imaging have limitations, including bulky probes and cell fixation.
• Stimulated Raman Scattering (SRS) imaging with bisarylbutadiyne (BADY) tagging offers an alternative but can alter drug properties.

Purpose of the Study:

• To develop a modified BADY tag that minimizes physicochemical differences from parent drugs while retaining Raman activity.
• To improve the accuracy of live-cell imaging for small-molecule drug distribution.
• To enhance drug development strategies through precise intracellular visualization.

Main Methods:

• Development of a modified BADY tag, methoxypyridazyl pyrimidyl butadiyne (MPDY), focusing on lipophilicity and membrane permeability.
• Live-cell Stimulated Raman Scattering (SRS) imaging to visualize drug distribution.
• Comparison of MPDY-tagged JQ1 analogue with BADY-tagged JQ1 analogue in HeLa cells.

Main Results:

• The modified MPDY tag significantly reduced deviations in physicochemical properties compared to the parent drug.
• MPDY tagging enabled clear visualization of intranuclear distribution of the JQ1 analogue in live HeLa cells.
• The original BADY tag did not provide a clear nuclear signal for the JQ1 analogue, indicating potential issues with its distribution or detection.

Conclusions:

• The developed MPDY tag is a promising tool for accurate live-cell SRS imaging of small-molecule drugs.
• This approach provides valuable insights into intracellular drug behavior, aiding in drug development.
• MPDY tagging represents a significant advancement for understanding and optimizing drug efficacy and safety.