Synthesis and Investigations of EGFR-Targeted Aza-BODIPY Conjugates

Two isothiocyanate-functionalized aza-boron−dipyrrome-thenes (aza-BODIPYs), 1 and 2, were covalently conjugated to the epidermal growth factor receptor (EGFR)-targeting Erlotinib, a tyrosine kinase inhibitor, and one of them also to the peptide cyclo(KLARLLT) known to target the extracellular domain of EGFR. In addition, d-glucosamine was also conjugated to aza-BODIPY for enhanced solubility and cell-targeting ability. Spectroscopic analysis showed that the conjugates exhibited absorption and emission in the near-infrared region (680−782 nm). The hybrid doubly targeted aza-BODIPY conjugate 1ab bearing both Erlotinib and the cyclic peptide shows a concentration-dependent interaction with the EGFR extracellular domain by SPR (Kd = 50.6 μM), while aza-BODIPY conjugate 2c competitively binds to the intracellular EGFR kinase. Autodock investigations revealed that the Erlotinib-containing conjugates bind to the active site of the intracellular kinase domain, while the hybrid aza-BODIPY conjugate binds both to the intracellular kinase and to the known binding site of cyclo(KLARLLT) on the extracellular domain of EGFR.