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A series of 1,3,5,7-tetraphenyl-aza-BODIPY dyes functionalized with electron-donating or withdrawing groups at the para-positions of the phenyl rings on either the 1,7- or 3,5-positions were synthesized and characterized. The electron-donating group selected was –NH2, while the electron-withdrawing groups spanned a range of strengths, from strong (-NO2) to moderate (-NH3+) and mild (-Ndouble bondCdouble bondS). The structural modifications were strategically implemented to investigate their impact on the dyes photophysical properties. Spectroscopic studies revealed that these dyes exhibit intense absorption and emission in the near-infrared (NIR) region (678–855 nm). The photophysical properties, including molar absorptivity, fluorescence quantum yield, and Stokes shift were found to depend significantly on both the electronic nature (donating/withdrawing) and positioning (1,7- vs. 3,5-) of the substituents. Complementary computational studies provided insights into the electronic structures and excited-state dynamics, corroborating experimental observations. Time-dependent density functional theory (TD-DFT) calculations revealed that the electron density distribution and the frontier orbitals’ energies and shapes were significantly influenced by the electronic effects of the substituent groups. This study underscores the tunability of aza-BODIPY dyes through rational molecular design, enabling precise control over their optical properties for tailored NIR applications. 

Recently, a series of 8(meso)-pyridyl-BODIPYs (2-pyridyl, 3-pyridyl, and 4-pyridyl) and their 2,6-substituted derivatives were synthesized and their structure and photophysical properties were studied both experimentally and computationally. One of the main observed trends was that the 2-pyridyl-BODIPYs were consistently less fluorescent than their 3-pyridyl and 4-pyridyl analogs, regardless of the 2,6-substituents. Herein, we extend our previous computational studies and model not only the ground but also the excited states of the entire series of previously synthesized meso-pyridyl-BODIPYs with the aim of explaining the observed differences in the emission quantum yields. To better understand the trends and the effect of 2- and 2,6-substitution on the photophysical and electron-density-related properties, we also model the ground and excited states of BODIPYs that were not synthesized experimentally, however represent a logical part of the series. We calculate a variety of molecular properties and propose that the experimentally observed low quantum yields for all 2-pyridyl-BODIPYs could be due to the very flat potential energy surfaces with respect to the rotation of the 2-pyridyl ring in the excited states, and the stability of a non-planar and significantly less fluorescent meso-2-pyridyl-BODIPY structure. 

A near-IR BODIPY was covalently conjugated via its isothiocyanate groups to one or two Erlotinib molecules, a known tyrosine kinase inhibitor (TKI), via triethylene glycol spacers, to produce two novel BODIPY-monoTKI and BODIPY-diTKI conjugates. The ability of these conjugates to target the intracellular domain of the epidermal growth factor receptor (EGFR) was investigated using molecular modeling, surface plasma resonance (SPR), EGFR kinase binding assay, time-dependent cellular uptake, and fluorescence microscopy. While both the BODIPY-monoTKI and the BODIPY-diTKI conjugates were shown to bind to the EGFR kinase by SPR and accumulated more efficiently within human HEp2 cells that over-express EGFR than BODIPY alone, only the BODIPY-monoTKI exhibited kinase inhibition activity. This is due to the high hydrophobic character and aggregation behavior of the BODIPY-diTKI in aqueous solutions, as shown by fluorescence quenching. Furthermore, the competition of the two Erlotinibs in the diTKI conjugate for the active site of the kinase, as suggested by computational modeling, might lead to a decrease in binding relative to the monoTKI conjugate. Nevertheless, the efficient cellular uptake and intracellular localization of both conjugates with no observed cytotoxicity suggest that both could be used as near-IR fluorescent markers for cells that over-express EGFR.