Porphyrins are available macroheterocyclic compounds which play an important role in diverse areas of scientific research owing to their unique photophysical, electrochemical, and optical properties . They have been widely studied in biomedical applications, as biosensors, bioimaging probes, and especially as photosensitizers (PSs) in photodynamic therapy (PDT) . PDT is a treatment modality that uses the combination of a non-toxic PS, oxygen, and light to treat diseases ranging from cancer to age-related macular degeneration and antibiotic-resistant infections . Currently, there are a few photosensitizers approved for clinical PDT such as Photofrin®, Foscan®, Lutex®, Tookad®, Purlytin®, Visudyne® and Laserphyrin® and experience in clinical use of PDT shows that this method belongs to one of promising directions in modern clinical oncology .

Further improvement of the PDT method requires the search for new photosensitizers having higher photoactivity, tumor selectivity, and high singlet oxygen quantum yield, as well as low in vivo toxicity . Therefore, some strategies have been developed to enhance the therapeutic efficiency of tetrapyrrole compounds since the delivery of a drug at a specific area in the body has vital importance to treat diseases. An alternative approach to solve this problem focused on the postfunctionalization of the porphyrin macrocycle with different linker groups capable for targeting conjugation of these porphyrins to other biological substrates and thus facilitate the conjugation with biomacromolecules . The modification of the porphyrin periphery with amino-, azido-, epoxy-, hydroxy-, and maleimido-functionalities is usually used for the covalent linkage of the porphyrin to the targeted biomacromolecule . In this context, fluorinated porphyrins have attracted considerable interest due to their biological properties such as low toxicity, metabolic stability, and cellular uptake. The introduction of a fluorine atom into the molecule is the feasibility to change drastically its biological properties and to modify the profile of biological activity due to optimum fluorine lipophylic properties, and enhanced interaction with lipid membranes . Pentafluorophenyl-substituted porphyrin systems are especially useful for the connection of various functionalities capable for coupling with biomolecules via the nucleophilic aromatic (SNAr) substitution reactions . A variety of nucleophiles such as amines , alcohols , thiols , and carboranes have been studied in selective SNAr substitution reactions of the p-fluorine atoms in meso-pentafluorophenyl-substituted porphyrins. Carboranes, due to their unique physical and chemical properties such as high chemical and biological stability , three-dimensional aromaticity , low toxicity , high hydrophobicity, and enriched boron content are perspective compounds in drug development . Owing to their stability, carboranes also may increase the in vivo stability and bioavailability of pharmaceuticals that might otherwise rapidly metabolize . The functionalization of porphyrins with carborane clusters provides dual-action photo(radio)sensitizers that are efficient for both PDT and boron neutron capture therapy (BNCT) . The preparation of compounds with dual therapeutic efficiency is of great importance since they improve the therapeutic effect of sensitizer by the action on the different cellular sites. Here, we report the synthesis and characterization of tris(carboranyl)porphyrins of A3B-type (where “B” corresponds to the substituent responsible for bioconjugate coupling) based on the transformations of 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin which was used as a basic compound for the synthesis of new boronated conjugates with functionalized linker groups suitable for bioconjugation or which may be efficient for PDT and BNCT improvement.

Scheme 1: Synthesis of porphyrins 2 and 3.

Scheme 2: Synthesis of carborane aminoporphyrin 5.

Scheme 3: Synthesis of carboranyl-substituted porphyrins 5–7.

It should be noted that the reaction of porphyrin 6 with NaN3 in DMSO at 20 °C for 48 h resulted in a mixture of azidoporphyrin 7 and amino derivative 5 which were separated by column chromatography on SiO2 to give porphyrin 7 and porphyrin 5 in 66% and 33% yields, respectively. The reduction of porphyrin 7 with SnCl2·2H2O in MeOH afforded porphyrin 5 in 92% yield.

Scheme 4: Synthesis of acylated carboranylporphyrins 11, 12, and 14.

Scheme 5: Synthesis of thio-substituted carboranylporphyrins 18–20.

The reactions proceeded readily in DMSO at room temperature for 10 min using anhydrous NaOAc as a base to afford the corresponding boronated porphyrin conjugates 18–20 in 80–87% yields.

Scheme 6: Synthesis of amino-substituted carboranylporphyrins 23, 24, and 26.

Conjugates 19, 23, 24, and 26 can be easily converted into hydrophilic charged entities by the protonation of the unsubstituted amino functionalities in their structure providing improved bioconjugation.

Table 1: Chemical shifts (ppm) and multiplicities (J, Hz) in 19F NMR spectra for all synthesized compounds.

The 11B NMR signals of compounds 5–7, 11, 12, 14, 18–20, 23, 24, and 26 are in the range from δ = −0.9 to −17.0 ppm confirming the closo-structure of the carborane polyhedra.

In this article a synthesis of A3B-type carboranylporphyrins as potential photosensitizers for PDT was developed based on the detailed study of the functionalization of a single pentafluorophenyl substituent in 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin with azido or amino functional groups. These compounds were used as a platform for the design of A3B-type carboranylporphyrins by the SNAr substitution reactions with 9-mercapto-m-carborane. As a result, tris(carboranyl)-substituted porphyrins containing pentafluorophenyl- or p-aminotetrafluorophenyl-substituents were synthesized and used in the reactions with a variety of thio- or amino-nucleophiles to form functionalized linkers capable to connect these porphyrins with biomolecules, thus improving their biomedical characteristics and theraputic efficacy for PDT and BNCT due to the combination of different substituents within porphyrin framework. Amide coupling of A3B-type carboranylporphyrin containing an amino functionality was supported by the design of conjugates containing maleimide and biotin substituents. The structures of prepared carboranylporphyrins were determined by UV–vis, IR, 1H 19F, 11B NMR spectroscopic data and MALDI mass spectrometry.