Abstract
Through a simple 1,3-cycloaddition reaction, three BODIPY-peptide conjugates that target the extracellular domain of the epidermal growth factor receptor (EGFR) were prepared and their ability for binding to EGFR was investigated. The peptide ligands K(N3)LARLLT and its cyclic analog cyclo(K(N3)larllt, previously shown to have high affinity for binding to the extracellular domain of EGFR, were conjugated to alkynyl-functionalized BODIPY dyes 1 and 2 via a copper-catalyzed click reaction. This reaction produced conjugates 3, 4, and 5 in high yields (70–82%). In vitro studies using human carcinoma HEp2 cells that overexpress EGFR demonstrated high cellular uptake, particularly for the cyclic peptide conjugate 5, and low cytotoxicity in light (~1 J·cm−2) and darkness. Surface plasmon resonance (SPR) results show binding affinity of the three BODIPY-peptide conjugates for EGFR, particularly for 5 bearing the cyclic peptide. Competitive binding studies using three cell lines with different expressions of EGFR show that 5 binds specifically to EGFR-overexpressing colon cancer cells. Among the three conjugates, 5 bearing the cyclic peptide exhibited the highest affinity for binding to the EGFR protein.
Highlights
We have previously reported the conjugation of boron dipyrromethenes (BODIPYs) to the epidermal growth factor receptor (EGFR)-L1 peptide via traditional amidation reactions [23], and nucleophilic additions to isothiocyanatofunctionalized fluorophores [21,22]
We reported the conjugation of this peptide to a porphyrin [19], phthalocyanine [20], and BODIPY dyes [21,22,23], using either traditional amidation methodologies or nucleophilic addition to isothiocyanato-functionalized fluorophores
The presence of the cyclic peptide in conjugate 5 induced the highest accumulation in HEp2 cells that overexpress EGFR of all compounds in this series
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The copper(I)-catalyzed azide-alkyne cycloadditions, or click reactions, have a multitude of suitable features, including mild reaction conditions, short completion times, simple to no purification required, and high stability of the resulting triazoles under various reaction conditions, such as to air and moisture Because of these benefits, the 1,3-dipolar cycloaddition is very attractive to researchers performing porphyrinoid conjugations for use in imaging and photodynamic therapy [32,33,34,35]. We report the synthesis of two BODIPYs bearing an alkynyl handle for conjugation via an azide-functionalized lysine side chain to two EGFR-L1 peptide derivatives that have shown increased EGFR binding affinity and stability relative to EGFR-L1
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