Recent studies of photosensitizers have increasingly focused on improving their aqueous solubility, reducing dark toxicity and enhancing photodynamic activity. In our work, we have synthesized and characterized a series of chlorin e6 derivatives varying in the number of galactose moieties in the molecule and way they are linked to the chlorin macrocycle. We established that the quantity and localization of galactose moieties in the macrocycle affects both dark and photoinduced cytotoxicity. All of the studied derivatives exhibited singlet oxygen quantum yield photogeneration comparable to that of the clinically approved chlorin e6 dimeglumine (Photoditazine®) with marginal exceeding. Although the incorporation of galactose moieties to the periphery of the chlorin macrocycle led to slightly decreased photostability of resulting derivatives, it did not significantly hinder their photodynamic activity. Moreover, cellular uptake of the obtained derivatives was significantly improved compared to that of Photoditazine®. Collectively, favorable spectral, photochemical, photobiological characteristics, along with improved aqueous solubility, suggest that chlorin e6 derivatives with peripheral galactose substituents are promising photosensitizers for clinical applications.

The work describes the synthesis and biological assays of a conjugate of a chlorin e6 cationic derivative with the reserve antimicrobial drug "Dioxidine". The influence of the alternate and joint introduction of the cationic N,Ndimethylpiperazinio and "Dioxidine" fragments into the macroheterocycle molecule on dark and photoinduced toxicity of the photosensitizers towards malignant HT-29, A549 and HeLa cells was studied. The introduction of the "Dioxidine" fragment into the cationic 13(1)-N,N-dimethylpiperaziniochlorin molecule is found to significantly reduce both the solubility of the photosensitizer in water and its photoinduced cytotoxicity. Our results clearly indicate that phototoxicity of the chlorins towards different tumor cells has a multidirectional nature.

A series of hydrophilic derivatives of chlorophyll a containing a digalactose fragment and fragments of mono-, di-, and triterpenoids attached to the porphyrin macrocycle through the amide bond were synthesized. The dark and photocytotoxicity of new terpene-containing chlorin-galactose conjugates were assessed in comparison with the chlorin-galactose derivative without the terpene substituent. It was found that the incorporation of the diterpenoid isosteviol increased the photoinduced cytotoxicity against the HeLa cells at a concentration of the target compound of 1 µmol L−1. A significant decrease in the survival of the HeLa, A549, and HT-29 cells occurred under the photoinduced exposure to all the studied compounds at a concentration of 10 µmol L−1.

In the present work, chlorophyll [Formula: see text] and deuteroporphyrin IX derivatives and copper (II) and silver (II) porphyrinates based on them were investigated for their ability to prevent oxidative stress in human HeLa cells exposed to paraquat (PQ) using fluorometric microculture cytotoxicity assay (FMCA). Among the compounds studied Ag-methylpyropheophorbide [Formula: see text] and Cu-methylpyropheophorbide [Formula: see text] contributed to a statistically significant increase in the survival of PQ-exposed cells. Additionally, ROS levels in HeLa cells were analyzed by flow cytometry using 2′,7′-dichlorofluorescein diacetate and Ag-methylpyropheophorbide [Formula: see text] and Cu-methylpyropheophorbide [Formula: see text] were shown to arrest PQ-mediated oxidative stress. Furthermore, these two compounds were tested for radioprotective activity in the experiment with irradiation of HeLa cells at doses of 3 Gy and 6 Gy. According to the FMCA results, the addition of Ag-methylpyropheophorbide [Formula: see text] and Cu-methylpyropheophorbide [Formula: see text] to the cell culture had no increase in cell survival compared to the positive control, demonstrating the absence of radioprotective effect of these compounds. It can be assumed that the difference in the effects of these porphyrin derivatives on cell survival is related to different localization of oxidative stress targets in cells exposed to PQ or ionizing radiation.

In this work, screening studies of the cytotoxic effect of chlorins with fragments of di-, tri-, and pentaethylene glycol at the macrocycle periphery in relation to HeLa, A549, and HT29 cells were performed. It is shown that, despite different hydrophobicity, all the compounds studied have a comparable photodynamic effect. The conjugate of chlorin e6 with pentaethylene glycol, which has the lowest tendency to association among the studied compounds with tropism for low density lipoproteins and the best characteristics of the formation of molecular complexes with Tween 80, has a significant difference in dark and photoinduced toxicity (ratio IC50(dark)/IC50(photo) approximately 2 orders of magnitude for all cell lines), which allows to hope for a sufficiently large "therapeutic window". A study of the interaction of this compound with HeLa cells shows that the substance penetrates the cell and, after red light irradiation induces ROS appearance inside the cell, associated, apparently, with the photogeneration of singlet oxygen. These data indicate that photoinduced toxic effects are caused by damage to intracellular structures as a result of oxidative stress. Programmed type of cell death characterized with caspase-3 induction is prevailing. So, the conjugate of chlorin e6 with pentaethylene glycol is a promising antitumor PS that can be successfully solubilized with Tween 80, which makes it suitable for further in vivo studies.

In this study, we described physico-chemical properties of novel nanoformulation of photosensitizer-pyropheophorbide α 17-diethylene glycol ester (XL) (chlorophyll α derivative), revealing insights into antitumor activity and maintaining quality, meeting the pharmaceutical approach of new nanoformulation design. Our formulation, based on poly(lactic-co-glycolic acid) (PLGA) nanoparticles, increased XL solubility and selective tumor-targeted accumulation. In our research, we revealed, for the first time, that XL binding to polyvinyl alcohol (PVA) enhances XL photophysical activity, providing the rationale for PVA application as a stabilizer for nanoformulations. Results of FTIR, DSC, and XRD revealed the physical interactions between XL and excipients, including PVA, indicating that the encapsulation maintained XL binding to PVA. The encapsulated XL exhibited higher photophysical activity compared to non-encapsulated substance, which can be attributed to the influence of residual PVA. Gamma-irradiation led to degradation of XL; however, successful sterilization of the samples was achieved through the filtration. Importantly, the encapsulated and sterilized XL retained cytotoxicity against both 2D and 3D tumor cell models, demonstrating the potential of the formulated NP–XL for photodynamic therapy applications, but lacked the ability to reactivate epigenetically silenced genes. These findings provide valuable insights into the design and characterization of PLGA-based nanoparticles for the encapsulation of photosensitizers.

In this work, new conjugates of galactose with dimeric derivatives of chlorophyll a with different hydrophilicity were synthesized. The change in the hydrophilicity of dimeric chlorins is achieved by introducing into the molecule one or two tertiary amino groups containing two galactose fragments as substituents at the nitrogen atom.

An experimental and theoretical study of structure and properties of chiral amphiphilic chlorin e6 13(N)-methylamide-15-methyl,17-alkyl esters (17-pentadecyl 1 and 17-phytyl 2) and their Ni complexes (Ni-1 and Ni-2) and their helical twisting efficiency in liquid crystal were carried out. Quantum chemical simulation of their structure was performed, the adequacy of which was established by comparing the calculated and experimental UV/Vis, CD, H-1 and C-13 NMR spectra as well as optical rotation angles. Low values of g-factors of dissymmetry for macroheterocycle (MHC) with the phytol substituent were experimentally revealed. The reason for this effect, associated with the transfer of the chirality from the stereogenic centers of the substituent to macrocyclic chromophore in the associate, was established by quantum-chemical calculation. Using polarization microscopy, the formation of chiral nematic phases was detected by doping a mixture of cyanobiphenyls with macroheterocycles 1, 2, Ni-1 and Ni-2. The values of the clearance temperature and helical pitch were measured, the slopes of phase diagrams beta and helical twisting power (HTP) were calculated. The orientation order parameters of dopants in liquid crystal (LC) were determined by polarization spectroscopy. The dielectric properties of LC-MHC systems were studied within the chiral nematics and isotropic phases, and the values of the Kirkwood's correlation factors were calculated. Using quantum chemical simulation of MHC solvates, the features of the influence of aliphatic chains structure and complex formation on the physical properties of induced mesophases were established.

Layered magnesium silicate was modified by water-insoluble chlorin e6 derivatives with two and three ethanolamine fragments on the periphery of the macrocycle by introducing chlorin e6 derivatives into the reaction medium as solutions in hydrochloric acid without the use of organic solvents. The modified layered silicates obtained are characterized by intense fluorescence along with photostability and exhibit photochemical activity in reactions of photosensitized oxidation of model pollutants like xanthene (rhodamine 6G) and azo dyes (methyl orange).

A deuteroporphyrin IX derivative with two D-galactose fragments with an ester bond between macrocycle and carbohydrate fragments was synthesized. The synthesis was done by esterifying both ester groups of deuteroporphyrin IX with diacetone-D-galactose using 2-chloro-1-methylpyridinium iodide (Mukayama reagent) followed by the removal of the isopropylidene protection of carbohydrate fragments by the action of aqueous trifluoroacetic acid to form the target derivative. The study of dark toxicity of the deuteroporphyrin IX derivative synthesized against HeLa cells allows us to conclude that galactose fragment introduction resulted in the cytotoxicity decrease as compared with the parent deuteroporphyrin IX but photoinduced cytotoxicity of the deuteroporphyrin IX derivative with two D-galactose fragments had increased in contrast to the deuteroporphyrin IX. It has been shown that oxidative stress due to ROS induction causes the photoinduced toxicity of the porphyrins studied.

Previously unknown hydrophilized derivatives of blood porphyrins bearing hydroxyethylamide moieties at the macrocycle periphery were synthesized via the reaction of ethanolamine with dimethyl esters of deuteroporphyrin IX, protoporphyrin IX, and mesoporphyrin IX.

A novel amphiphilic cationic chlorin e(6) derivative was investigated as a promising photosensitizer for photodynamic therapy. Two cationic -N(CH3)(3)(+) groups on the periphery of the macrocycle provide additional hydrophilization of the molecule and ensure its electrostatic binding to the mitochondrial membranes and bacterial cell walls. The presence of a hydrophobic phytol residue in the same molecule results in its increased affinity towards the phospholipid membranes while decreasing its stability towards aggregation in aqueous media. In organic media, this chlorin e(6) derivative is characterized by a singlet oxygen quantum yield of 55%. Solubilization studies in different polymer- and surfactant-based supramolecular systems revealed the effective stabilization of this compound in a photoactive monomolecular form in micellar nonionic surfactant solutions, including Tween-80 and Cremophor EL. A novel cationic chlorin e(6) derivative also demonstrates effective binding towards serum albumin, which enhances its bioavailability and promotes effective accumulation within the target tissues. Laser confocal scanning microscopy demonstrates the rapid intracellular accumulation and distribution of this compound throughout the cells. Together with low dark toxicity and a rather good photostability, this compound demonstrates significant phototoxicity against HeLa cells causing cellular damage most likely through reactive oxygen species generation. These results demonstrate a high potential of this derivative for application in photodynamic therapy.

In this review, we generalize the research results obtained by Russian scientists in the last 10-15 years for porphyrins, related compounds, and their metal complexes with a pronounced application potential. The main attention is paid to the analysis of relationships between the spectral, catalytic, and sensor properties of tetrapyrrole compounds and the structure of peripheral substituents and axial ligands and the nature of the coordinating metal atom.

В данном обзоре обобщены результаты исследований в области порфиринов, родственных соединений и их металлокомплексов с явно выраженным прикладным потенциалом, выполненных российскими учеными в последние 10-15 лет. Основное внимание сосредоточено на анализе взаимосвязи спектральных, каталитических и сенсорных свойств тетрапиррольных соединений со строением экваториального порфиринового и аксиальных лигандов и природой координирующего атома металла.

The conjugates of natural and synthetic porphyrins with carbohydrates are known to be promising antitumor photo -sensitizers (PS). The presence of monosaccharide fragments at the periphery of the porphyrin macrocycle leads to an increase in bioavailability and increases their uptake by cancer cells. We synthesized new hydrophilic conjugates of chlorin e6 with fructose by alkylation of the amino groups of chlorin e6 amides with one and two ethylenediamine or hexamethylenediamine fragments on the macrocycle periphery with triflate of 2,3:4,5-di-O-isopropylidene-beta-D-fructopyranose, followed by removal of diisopropylidene protection by 70% aqueous trifluoroacetic acid. In all cases, monoalkylation occurs, which allows the chemoselective insertion of one fructose fragment for each amino group present in the initial chlorin. For most of the studied compounds, it is possible to obtain a solution containing at least 0.2 mg/mL without the use of auxiliary substances, which indicates the possibility of obtaining water-soluble forms. The synthesized conjugates were shown to exhibit pronounced photodynamic activity at concentrations at which dark cytotoxic effect is not observed (HeLa, A549, HT-29 cancer cell cultures were used as test objects).

The experimental and theoretical study of the influence of metal complexing on geometry, aromaticity, chirality, and the ability to twist the nematic phase by complexes based on modified natural chlorin e6 was carried out. The geometry optimization of the chlorin e6 13(N)-methylamide-15,17-dimethyl ester (MADMECl) and its Zn, Cu, and Ni complexes by DFT (CAM-B3LYP/6–31 G(d,p) functional) method was performed. Based on these calculations, the acoplanarity degree of the macrocyclic ligand and the distortion energy of its dianion were estimated, which allowed the arrangement of the MADMECl complexes in the series Ni > Cu > Zn. Aromaticity was evaluated using the NICS criterion (nuclear independent chemical shift). An increase in the degree of aromaticity of the macrocycle upon complex formation was established. At the same time, the aromaticity of the inner conjugation contour corresponds to the same series as the acoplanarity, while the outer π-delocalization is characterized by the reverse sequence. An experimental evaluation of the electron circular dichroism of the Soret and the Q-bands, as well as the g-factor of dissymmetry, was carried out. The growth of these parameters with an increase in the degree of acoplanarity and aromaticity of the internal conjugation contour was determined. The induction of helical phases in mixtures of nematic liquid crystals (LCs) based on cyanobiphenyls and MADMECl macrocyclic metal complexes was studied by polarization microscopy, and the clearance temperatures and helix pitch of the mesophases were measured. A strong effect of the metal on the phase transition temperature and helical twisting power was established.

Water-soluble chlorin e 6 cationic derivatives with one and two galactose fragments at the quaternized nitrogen atom were synthesized, and the dark and photoinduced cytotoxicity of the obtained compounds was evaluated.

This review presents a wide range of tetrapyrrole photosensitizers used for photodynamic therapy (PDT), antimicrobial photodynamic therapy, photoinactivation of pathogens. Methods of synthesis and design of new photosensitizers with greater selectivity of accumulation in tumor tissue and increased photoinduced antitumor activity are considered. The issues of studying the properties of new photosensitizers, their photoactivity, the ability to generate singlet oxygen, and the possibility of using targeted photodynamic therapy in clinical practice are discussed. The review examines the work on PDT by national and foreign researchers.

The esterification of carboxyl groups of deuteroporphyrin IX and transesterification of ester groups of dimethyl ester of deuteroporphyrin IX with di-, tetra-, hexaethylene glycols were studied. It is shown, that depending on the oli-goethylene glycol and the reaction conditions used, both derivatives with two polyester moieties in the molecule (one for each propionate substituent) and derivatives with one polyester moiety linking the propionate substituents of por-phyrin can be obtained.