Conjugates of Tetrapyrrolic Macrocycles as Potential Anticancer Target-Oriented Photosensitizers.

Photodynamic therapy is a minimally invasive treatment of tumors using photosensitizers, light, and reactive oxygen species, which can destroy cellular structures. With the development of photodynamic therapy, significant efforts have been made to create new efficient photosensitizers with improved delivery to cells, stability, and selectivity against cancer tissues. Naturally occurring tetrapyrrolic macrocycles, such as porphyrins and chlorins, are very attractive as photosensitizers, and their structural modification and conjugation with other biologically active molecules are promising approaches for creating new photosensitizers specifically targeting cancer cells. The present review aims to highlight recent developments in the design, preparation, and investigation of complex conjugates of tetrapyrrolic macrocycles, which can potentially be used as sensitizers for target-oriented photodynamic therapy of cancer. In this review, we discuss the structure, photodynamic effect, and anticancer activity of the following conjugates of tetrapyrrolic macrocycles: (1) conjugates obtained by modifying peripheral substituents in porphyrins and chlorins; (2) conjugates of porphyrins and chlorins with lipids, carbohydrates, steroids, and peptides; (3) conjugates of porphyrins and chlorins with anticancer drugs and some other biologically active molecules; (4) metal-containing conjugates. The question of how the conjugate structure affects its specificity, internalization, localization, and photoinduced toxicity within cancer cells is the focus of this review.

Synthesis of Photosensitizers Based on Tetrapyrrolic Macrocycles for Combination with Antibiotics: Dual Inactivation of Bacteria.

The combination of photodynamic therapy with antibiotics or antimicrobial peptides for inactivation of bacteria is an area of growing interest due to the synergistic effect already observed by many authors. It has been shown that the efficiency of this dual antimicrobial therapy is highly dependent on the structure of the photosensitizer, being tetrapyrrolic macrocycles the ones with most promising results. There are a few review articles in the recent literature describing the main microbiological results concerning this dual inactivation of bacteria, but none of them focus on the synthetic processes of these photosensitizers and their remarkable chemical versatility. Therefore, herein we present an overview on synthetic methodologies for preparation of tetrapyrrolic macrocycles and their conjugates with antibiotics or antimicrobial peptides, for use in dual inactivation of bacteria. This review will be divided in two sections concerning the physical or covalent combinations of PS with antibiotic/cationic peptides, followed by brief critical analysis on their corresponding antimicrobial outcomes.

New nitroindazole-porphyrin conjugates: Synthesis, characterization and antibacterial properties.

The synthesis of new porphyrin-indazole hybrids by a Knoevenagel condensation of 2-formyl-5,10,15,20-tetraphenylporphyrin and N-methyl-nitroindazolylacetonitrile derivatives is reported. The target compounds were isolated in moderate to good yields (32-57%) and some of the isolated porphyrin-indazole conjugates showed good performance in the generation of singlet oxygen when irradiated with visible light. Their efficiency as photosensitizers in the photoinactivation of methicillin resistant Staphylococcus aureus-MRSA was evaluated. All derivatives showed to be able to photoinactivate the MRSA bacteria. Compound 3a appears to be the most promising photosensitiser (PS) in the photoinactivation of these bacteria, despite being the least efficient in singlet oxygen generation. The addition of potassium iodide (KI) significantly potentiated the antimicrobial Photodynamic Therapy (aPDT) process mediated by all the analysed porphyrin-indazole conjugates. The combined action of nitroindazole-porphyrins with potassium iodide (KI) action appears to be promising in the photoinactivation of MRSA.

Reactive Cobalt⁻Oxo Complexes of Tetrapyrrolic Macrocycles and N-based Ligand in Oxidative Transformation Reactions.

High-valent cobalt⁻oxo complexes are reactive transient intermediates in a number of oxidative transformation processes e.g., water oxidation and oxygen atom transfer reactions. Studies of cobalt⁻oxo complexes are very important for understanding the mechanism of the oxygen evolution center in natural photosynthesis, and helpful to replicate enzyme catalysis in artificial systems. This review summarizes the development of identification of high-valent cobalt⁻oxo species of tetrapyrrolic macrocycles and N-based ligands in oxidation of organic substrates, water oxidation reaction and in the preparation of cobalt⁻oxo complexes.

Recent Advances in Catalyzed Sequential Reactions and the Potential Use of Tetrapyrrolic Macrocycles as Catalysts.

Complexes of porphyrins and of other similar tetrapyrrolic macrocycles are extensively explored as catalysts for different chemical processes, and the development of solid catalysts for heterogeneous processes using molecules with the ability to act as multifunctional catalysts in one-pot reactions is increasing and can lead to the wider use of this class of molecules as catalysts. This mini review focuses on the application of this class of complexes as catalysts in a variety of sequential one-pot reactions.

Conjugates of 17-substituted testosterone and epitestosterone with pyropheophorbide a differing in the length of linkers.

Conjugates of 17α-substituted testosterone (1 and 2) and 17ß-substituted epitestosterone (3 and 4) with pyropheophorbide a were synthesized. The scheme consisted of synthesis of 17α-hydroxy-3-oxopregn-4-en-21-oic and 17ß-hydroxy-3-oxopregn-4-en-21-oic acids, and their coupling with pyropheophorbide a by means of either ethylene diamine, or 1,5-diamino pentane linkers. Mutual influence of steroidal and macrocyclic fragments in conjugates molecules was dependent on configuration of C17 and length of linker, that was established by analysis of 1H NMR spectra and molecular models of conjugates. Studies of interaction of conjugates with prostate carcinoma cells revealed that their uptake and internalization were independent on the androgen receptor activity, but dependent on the structure of conjugates, decreasing in the following row: 3 > 4 ≥ 1 > 2. Conjugates significantly decreased the LNCaP and PC-3 cells growth at 96 h incubation. Epitestosterone derivatives 3 and 4 also showed superior anti-proliferative activity versus testosterone ones. Conformationally more rigid conjugates 1 and 3, comprising short linkers, were more active than those with long linkers; conjugate 3 was the most potent.

Comparative Study of the Optical and Textural Properties of Tetrapyrrole Macrocycles Trapped Within ZrO2, TiO2, and SiO2 Translucent Xerogels.

The entrapping of physicochemical active molecules inside mesoporous networks is an appealing field of research due to the myriad of potential applications in optics, photocatalysis, chemical sensing, and medicine. One of the most important reasons for this success is the possibility of optimizing the properties that a free active species displays in solution but now trapped inside a solid substrate. Additionally it is possible to modulate the textural characteristics of substrates, such as pore size, specific surface area, polarity and chemical affinity of the surface, toward the physical or chemical adhesion of a variety of adsorbates. In the present document, two kinds of non-silicon metal alkoxides, Zr and Ti, are employed to prepare xerogels containing entrapped tetrapyrrolic species that could be inserted beforehand in analogue silica systems. The main goal is to develop efficient methods for trapping or binding tetrapyrrole macrocycles inside TiO2 and ZrO2 xerogels, while comparing the properties of these systems against those of the SiO2 analogues. Once the optimal synthesis conditions for obtaining translucent monolithic xerogels of ZrO2 and TiO2 networks were determined, it was confirmed that these substrates allowed the entrapment, in monomeric form, of macrocycles that commonly appear as aggregates within the SiO2 network. From these experiments, it could be determined that the average pore diameters, specific surface areas, and water sorption capacities depicted by each one of these substrates, are a consequence of their own nature combined with the particular structure of the entrapped tetrapyrrole macrocycle. Furthermore, the establishment of covalent bonds between the intruding species and the pore walls leads to the obtainment of very similar pore sizes in the three different metal oxide (Ti, Zr, and Si) substrates as a consequence of the templating effect of the encapsulated species.

Possible in vivo mechanisms involved in photodynamic therapy using tetrapyrrolic macrocycles

Photodynamic therapy (PDT) mediated by oxidative stress causes direct tumor cell damage as well as microvascular injury. To improve this treatment new photosensitizers are being synthesized and tested. We evaluated the effects of PDT with 5,10,15,20-tetrakis(4-methoxyphenyl)-porphyrin (TMPP) and its zinc complex (ZnTMPP) on tumor levels of malondialdehyde (MDA), reduced glutathione (GSH) and cytokines, and on the activity of caspase-3 and metalloproteases (MMP-2 and -9) and attempted to correlate them with the histological alterations of tumors in 3-month-old male Wistar rats, 180 ± 20 g, bearing Walker 256 carcinosarcoma. Rats were randomly divided into five groups: group 1, ZnTMPP+irradiation (IR) 10 mg/kg body weight; group 2, TMPP+IR 10 mg/kg body weight; group 3, 5-aminolevulinic acid (5-ALA+IR) 250 mg/kg body weight; group 4, control, no treatment; group 5, only IR. The tumors were irradiated for 15 min with red light (100 J/cm², 10 kHz, 685 nm) 24 h after drug administration. Tumor tissue levels of MDA (1.1 ± 0.7 in ZnTMPP vs 0.1 ± 0.04 nmol/mg protein in control) and TNF-α (43.5 ± 31.2 in ZnTMPP vs 17.3 ± 1.2 pg/mg protein in control) were significantly higher in treated tumors than in controls. Higher caspase-3 activity (1.9 ± 0.9 in TMPP vs 1.1 ± 0.6 OD/mg protein in control) as well as the activation of MMP-2 (P < 0.05) were also observed in tumors. These parameters were correlated (Spearman correlation, P < 0.05) with the histological alterations. These results suggest that PDT activates the innate immune system and that the effects of PDT with TMPP and ZnTMPP are mediated by reactive oxygen species, which induce cell membrane damage and apoptosis.