Late-Stage Functionalization of Peptides and Cyclopeptides Using Organozinc Reagents

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Peptide Chemistry

Background:

• Late-stage functionalization is crucial for modifying complex molecules like peptides.
• Developing efficient cross-coupling reactions for peptide modification remains a challenge.

Purpose of the Study:

• To report a new late-stage functionalization method for small peptides and cyclopeptides.
• To investigate the impact of this modification on peptide solubility and cell-membrane permeability.

Main Methods:

• Utilized Negishi cross-coupling reactions.
• Coupled iodotyrosine- or iodophenylalanine-containing peptides with aryl-, heteroaryl-, and alkylzinc pivalates or halides.
• Performed in silico and in vitro determinations of membrane permeability parameters.

Main Results:

• Successfully achieved late-stage functionalization of peptides and cyclopeptides.
• Observed improved solubility in modified cyclopeptides, particularly with the introduction of polar pyridyl units.
• Maintained cell-membrane permeability in most modified cyclopeptides.

Conclusions:

• The reported Negishi cross-coupling is an effective method for late-stage peptide functionalization.
• Introduction of polar groups can enhance peptide solubility without compromising cell-membrane permeability.
• This method holds potential for developing new peptide-based therapeutics.