Solid-Phase Multicomponent Synthesis of 3-Substituted Isoindolinones Generates New Cell-Penetrating Probes as Drug...

Area of Science:

• Organic Synthesis
• Medicinal Chemistry
• Bioconjugation

Background:

• Multicomponent reactions offer efficient synthetic routes.
• Solid-phase synthesis facilitates purification and modularity.
• Fluorescent probes are valuable tools for cell biology and drug delivery.

Purpose of the Study:

• To develop a modular solid-phase multicomponent reaction for synthesizing 3-substituted isoindolinone derivatives.
• To create novel fluorescent peptide-based probes for cell imaging and drug delivery.
• To evaluate the cellular uptake and biological activity of the synthesized probes.

Main Methods:

• A one-pot solid-phase multicomponent reaction involving a chiral β-keto lactam, aldehyde, isocyanide, and dienophile.
• Microwave irradiation was employed for reaction optimization.
• The reaction was adapted for conjugation to a programmed cell death-inducing peptide, (KLAKLAK)2.

Main Results:

• Chiral 3-substituted isoindolinones were synthesized efficiently.
• The resulting peptide conjugates exhibited significant fluorescence with large Stokes shifts and rapid cell penetration.
• The fluorescent probes were effectively internalized by cells, inducing programmed cell death and demonstrating potential as drug carriers.

Conclusions:

• A versatile modular solid-phase multicomponent reaction was established for isoindolinone synthesis.
• Novel fluorescent peptide probes were generated with excellent cell-penetrating and imaging capabilities.
• These probes show promise as cell sensors and targeted drug delivery systems for inducing programmed cell death.