Fatty Acid Conjugates of Toluidine Blue O as Amphiphilic Photosensitizers: Synthesis, Solubility, Photophysics and Photochemical Properties^†

Abstract

Toluidine blue O (TBO) is a water‐soluble photosensitizer that has been used in photodynamic antimicrobial and anticancer treatments, but suffers from limited solubility in hydrophobic media. In an effort to incrementally increase TBO’s hydrophobicity, we describe the synthesis of hexanoic (TBOC6) and myristic (TBOC14) fatty acid derivatives of TBO formed in low to moderate percent yields by condensation with the free amine site. Covalently linking 6 and 14 carbon chains led to modifications of not only TBO’s solubility, but also its photophysical and photochemical properties. TBOC6 and TBOC14 derivatives were more soluble in organic solvents and showed hypsochromic shifts in their absorption and emission bands. The solubility in phosphate buffer solution was low for both TBOC6 and TBOC14, but unexpectedly slightly greater in the latter. Both TBOC6 and TBOC14 showed decreased triplet excited‐state lifetimes and singlet oxygen quantum yields in acetonitrile, which was attributed to heightened aggregation of these conjugates particularly at high concentrations due to the hydrophobic “tails.” While in diluted aqueous buffer solution, indirect measurements showed similar efficiency in singlet oxygen generation for TBOC14 compared to TBO. This work demonstrates a facile synthesis of fatty acid TBO derivatives leading to amphiphilic compounds with a delocalized cationic “head” group and hydrophobic “tails” for potential to accumulate into biological membranes or membrane/aqueous interfaces in PDT applications.

Binding of toluidine blue-myristic acid derivative to cucurbit[7]uril and human serum albumin: computational and biophysical insights towards a biosupramolecular assembly

“…These results are in agreement with previous studies using other derivatives of TBO. 43 In the presence of HSA and/or CB[7], the absorption spectra of TBOMyr did not change (Fig. 2A), while the emission intensity increased significantly (Fig.…”

“…The enhancement effect provided by CB[7] was much larger than previously reported for the TBOC14 derivative lacking the terminal carboxylic group. 43 Additionally, the TBOMyr derivative showed two fluorescence lifetimes, which increased in the presence of CB[7], whereas in the presence of HSA a third component with a much longer lifetime appeared (Table 1). The photophysical data is consistent with complexation by the protein and the macrocycle, which will be explored in detail below by computational and experimental techniques.…”

“…54,55 The functional B97D was chosen based on its good performance in a previous study for TBO and TBO aliphatic derivates by TD-DFT calculations. 43,56 The UV-Visible spectra were obtained by singlet–singlet vertical transitions of Franck–Condon type using 30 excited states. The absorption spectra were calculated in the solution phase (water), using the conductor-like polarizable continuum model (C-PCM) with the standard parameters water.…”

“…Recently, we studied the photophysics and supramolecular interactions of TBO amphiphilic derivatives bearing different length alkyl chains (TBOC6 and TBOC14) with CB[7] and HSA, and their effect on phototoxicity in cultured tumoral cells. 42,43 In the present work, we investigated the binding of a new TBO derivative, namely TBOMyr (Chart 1D), containing a 14-carbon atom chain and a terminal carboxylate group, mimicking the structure of Myr. This is relevant since our previous studies showed the favorable inclusion of the hydrophobic tail of the compounds in CB[7], which was not desired, leading to mild effect on their photophysics/photochemistry.…”