From Ugi Multicomponent Reaction to Linkers for Bioconjugation.

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Bioconjugation Chemistry

Background:

• Bioconjugation is crucial for developing targeted therapies using biomolecules like antibodies.
• Existing linkers may not meet the demands for next-generation targeted pharmaceuticals.
• There is a need for versatile and stable linkers for applications such as antibody-drug conjugates (ADCs).

Purpose of the Study:

• To design and develop a novel, versatile, and stable linker for bioconjugation.
• To focus on applications in antibody-drug conjugates (ADCs).
• To demonstrate the efficiency of the developed linker in conjugation strategies.

Main Methods:

• Utilized the Ugi multicomponent reaction for linker synthesis.
• Chemically modified Ugi adducts to create bifunctional linkers.
• Developed and tested a conjugation strategy to validate linker efficiency.

Main Results:

• Successfully designed and synthesized a stable N-alkylated α,α-dialkyl dipeptide linker.
• Demonstrated the versatility of the linker for bioconjugation applications.
• Prepared a novel cytotoxic anti-HER2 antibody-drug conjugate (ADC) using the Ugi-linker approach.

Conclusions:

• The Ugi-linker approach provides a versatile and efficient method for creating novel bioconjugates.
• The developed dipeptide linker is suitable for constructing advanced antibody-drug conjugates.
• This strategy holds promise for the development of next-generation targeted pharmaceuticals.