trans-Bisglycoconjugation is an Efficient and Robust Architecture for PDT Photosensitizers Based on 5,10,15,20-Tetrakis(pentafluorophenyl)porphyrin Derivatives

Abstract

To examine the versatility of the trans-bisglycoconjugation architecture for 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin (TFPP) derivative-based photodynamic therapy (PDT), 25 porphyrin derivatives bearing d-glucopyranose moieties were prepared, and their in vitro photocytotoxicities were examined. trans-Bisglycoconjugated TFPP derivatives exerted the best photocytotoxicity among TFPP derivatives in the same category, regardless of the central metal ion and the type of glycoconjugation. trans-Bisglycoconjugated free-base TFPP bearing β-d-glucopyranosylthio groups (trans-H22SGlc) was found to be the most potent photosensitizer, not only in HeLa cells (EC50 < 5 nM), but also in highly metastatic cancer cell lines such as B16-BL6 melanoma cells (EC50 < 10 nM). UV–vis and dynamic light-scattering measurements suggested that trans-bisglycoconjugated TFPP derivatives formed relatively large J-aggregates in an aqueous solution. trans-Bisglycoconjugated TFPP derivatives exhibited greater uptake by HeLa cells than those with different glycoconjugation patterns, with the exception of Zn(II) complexes. trans-Bisglycoconjugated TFPP derivatives efficiently generated hydrogen peroxide and hydroxyl radical by a type I photoreaction, while no significant differences were found in the efficiency of singlet oxygen generation by a type II photoreaction. These unique characteristics of trans-bisglycoconjugated TFPP derivatives support the conclusion that trans-bisglycoconjugation is a highly efficient and robust architecture for TFPP-based PDT development.

Synthesis, Photophysical Properties, and Biological Evaluation of trans-Bisthioglycosylated Tetrakis(fluorophenyl)chlorin for Photodynamic Therapy

“…The EC 50 value of 7 was 1−5 nM which was almost the same as that of 3 (1−5 nM) and lower than that of 8 (50−100 nM). Similar to the photocytotoxicities of a series of glycosylated porphyrins, 28,30 transbisthioglycosylated chlorin 7 exerted greater photocytotoxicity than that of fully glycosylated chlorin 8. The superiority of 7 compared with 3 was significant at wavelengths >600 nm (Figure 2b).…”

“…The enhanced uptake of trans-bisthioglycosylated chlorin 7 compared with that of fully glycosylated chlorin 8 is similar to that of the glycosylated porphyrin series. 28,30 Therefore, cellular uptake was controlled solely by the peripheral glycosylation pattern and not by the core structure. In contrast, the absorption of light was mainly due to the core structure.…”

Nucleophilic Aromatic Substitution on Pentafluorophenyl‐Substituted Dipyrranes and Tetrapyrroles as a Route to Multifunctionalized Chromophores for Potential Application in Photodynamic Therapy

“…Owing to their polar substituents (OH and NH) and the hydrophobic porphyrin skeleton, these compounds exhibit a ‘medium’ polarity, which is also found in clinically applied photosensitizers, such as Temoporfin or TOOKAD . Moreover, trans ‐A 2 B 2 ‐porphyrins that carry polar substituents have been reported to exhibit a high PDT activity . Hence, compounds 12e , 12h , 12i , and the bisamino‐substituted precursor 11b were selected for testing against four tumor cell lines: human epidermoid carcinoma cell lines A431 and A253, squamous carcinoma cell line CAL‐27, and colorectal adenocarcinoma cell line HT29 (Figure ).…”

“…[50] Moreover, trans-A 2 B 2 -porphyins carrying polar substituents have been reported to exhibit a high PDT activity. [51] Hence, compounds 12e, 12h, 12i and the bisamino-substituted precursor 11b were selected for testing against four tumor cell lines (Figure 5a-d): Human epidermoid carcinoma cell lines A431 and A253, respectively, squamous carcinoma cell line CAL-27, and colorectal adenocarcinoma cell line HT29. In brief, cells were incubated for 24 h with a solution of either 0, 2 or 10 µmol/L concentration of the photosensitizer and medium, then the medium was changed (to assure that only photosensitizer taken up by the cells contributes to the effect) and the cells were irradiated with light of 652 nm (corresponding to the longest wavelength absorption band of the porphyrins); after another incubation period (24 h) with medium the vitality of the cells was determined using the XTT-test (see experimental section for details).…”

Synthesis of Water-Soluble Thioglycosylated trans-A2B2 Type Porphyrins: Cellular Uptake Studies and Photodynamic Efficiency

“…The malignant cells are known to overexpress carbohydrate-binding proteins. − The porphyrin-based molecules can be targeted toward cell surface receptors particularly known as carbohydrate-binding lectins, by linking hexose sugars/oligosaccharides on the molecules. − Glycoconjugated porphyrinoids have been nicely summarized in the recent review by Drain and co-workers, such molecules have shown good solubility and higher cellular uptake due to enhanced interactions with tumor cell receptors . Thus, carbohydrate–porphyrin conjugates are promising candidates for PDT; attachment of sugars make them amphiphilic in nature and helps in their cellular uptake in tumor cells. − However, the ongoing research on novel glycoporphyrin conjugates for PDT is challenging, due to the lack of straightforward synthetic protocols to prepare such molecules in large quantities. The well-established methods of porphyrin syntheses reported by Lindsey and co-workers and Alder and co-workers are not favorable to prepare glycosylated porphyrins in good yields. , The available glycoconjugates of porphyrins were synthesized either by condensation of pyrrole with carbohydrate-linked benzaldehydes , or by using click chemistry to link hexose sugars to the functionalized porphyrin through triazole units. , Tetrasubstituted O -linked and S -linked glycoporphyrin conjugates were prepared by substituting the para -position of the meso -aryl groups of porphyrins; this method is mostly used to make A 4 type carbohydrate–porphyrins conjugates. , Glycosylated porphyrins have exquisite photophysical properties, and literature supports the hypothesis of improved cellular uptake and photocytotoxicity for glycosylated porphyrins as compared to nonfunctionalized systems. , The biological behavior of the reported glycosylated porphyrins differs depending upon the number of monosaccharide units attached at the meso -positions, which affect the cellular uptake and photocytotoxicity toward cancer cells .…”