Efficient Strategies to Use ß-Cationic Porphyrin-Imidazolium Derivatives in the Photoinactivation of Methicillin-Resistant Staphylococcus aureus.

Bacterial resistance to antibiotics is a critical global health issue and the development of alternatives to conventional antibiotics is of the upmost relevance. Antimicrobial photodynamic therapy (aPDT) is considered a promising and innovative approach for the photoinactivation of microorganisms, particularly in cases where traditional antibiotics may be less effective due to resistance or other limitations. In this study, two ß-modified monocharged porphyrin-imidazolium derivatives were efficiently incorporated into polyvinylpyrrolidone (PVP) formulations and supported into graphitic carbon nitride materials. Both porphyrin-imidazolium derivatives displayed remarkable photostability and the ability to generate cytotoxic singlet oxygen. These properties, which have an important impact on achieving an efficient photodynamic effect, were not compromised after incorporation/immobilization. The prepared PVP-porphyrin formulations and the graphitic carbon nitride-based materials displayed excellent performance as photosensitizers to photoinactivate methicillin-resistant Staphylococcus aureus (MRSA) (99.9999% of bacteria) throughout the antimicrobial photodynamic therapy. In each matrix, the most rapid action against S. aureus was observed when using PS 2. The PVP-2 formulation needed 10 min of exposure to white light at 5.0 µm, while the graphitic carbon nitride hybrid GCNM-2 required 20 min at 25.0 µm to achieve a similar level of response. These findings suggest the potential of graphitic carbon nitride-porphyrinic hybrids to be used in the environmental or clinical fields, avoiding the use of organic solvents, and might allow for their recovery after treatment, improving their applicability for bacteria photoinactivation.

opp-Dibenzoporphyrin Pyridinium Derivatives as Potential G-Quadruplex DNA Ligands.

Since the occurrence of tumours is closely associated with the telomerase function and oncogene expression, the structure of such enzymes and genes are being recognized as targets for new anticancer drugs. The efficacy of several ligands in telomerase inhibition and in the regulation of genes expression, by an effective stabilisation of G-quadruplexes (G4) DNA structures, is being considered as a promising strategy in cancer therapies. When evaluating the potential of a ligand for telomerase inhibition, the selectivity towards quadruplex versus duplex DNA is a fundamental attribute due to the large amount of double-stranded DNA in the cellular nucleus. This study reports the evaluated efficacy of three tetracationic opp-dibenzoporphyrins, a free base, and the corresponding zinc(II) and nickel(II) complexes, to stabilise G4 structures, namely the telomeric DNA sequence (AG3(T2AG3)3). In order to evaluate the selectivity of these ligands towards G4 structures, their interaction towards DNA calf thymus, as a double-strand DNA sequence, were also studied. The data obtained by using different spectroscopic techniques, such as ultraviolet-visible, fluorescence, and circular dichroism, suggested good affinity of the free-base porphyrin and of its zinc(II) complex for the considered DNA structures, both showing a pattern of selectivity for the telomeric G4 structure. A pattern of aggregation in aqueous solution was detected for both Zn(II) and Ni(II) metallo dibenzoporphyrins and the ability of DNA sequences to induce ligand disaggregation was observed.

A Comparative Evaluation of the Photosensitizing Efficiency of Porphyrins, Chlorins and Isobacteriochlorins toward Melanoma Cancer Cells.

Skin cancer is one of the cancers that registers the highest number of new cases annually. Among all forms of skin cancer, melanoma is the most invasive and deadliest. The resistance of this form of cancer to conventional treatments has led to the employment of alternative/complementary therapeutic approaches. Photodynamic therapy (PDT) appears to be a promising alternative to overcome the resistance of melanoma to conventional therapies. PDT is a non-invasive therapeutic procedure in which highly reactive oxygen species (ROS) are generated upon excitation of a photosensitizer (PS) when subjected to visible light of an adequate wavelength, resulting in the death of cancer cells. In this work, inspired by the efficacy of tetrapyrrolic macrocycles to act as PS against tumor cells, we report the photophysical characterization and biological assays of isobacteriochlorins and their corresponding chlorins and porphyrins against melanoma cancer cells through a photodynamic process. The non-tumoral L929 fibroblast murine cell line was used as the control. The results show that the choice of adequate tetrapyrrolic macrocycle-based PS can be modulated to improve the performance of PDT.

New Bis-Cyclometalated Iridium(III) Complexes with ß-Substituted Porphyrin-Arylbipyridine as the Ancillary Ligand: Electrochemical and Photophysical Insights.

An efficient synthetic access to new cationic porphyrin-bipyridine iridium(III) bis-cyclometalated complexes was developed. These porphyrins bearing arylbipyridine moieties at ß-pyrrolic positions coordinated with iridium(III), and the corresponding Zn(II) porphyrin complexes were spectroscopically, electrochemically, and electronically characterized. The features displayed by the new cyclometalated porphyrin-bipyridine iridium(III) complexes, namely photoinduced electron transfer process (PET), and a remarkable efficiency to generate 1O2, allowing us to envisage new challenges and opportunities for their applications in several fields, such as photo(catalysis) and photodynamic therapies.

Ortho Isomeric Mn(III) N-Alkyl- and Alkoxyalkylpyridylporphyrins-Enhancers of Hyaluronan Degradation Induced by Ascorbate and Cupric Ions.

High levels of hyaluronic acid (HA) in tumors correlate with poor outcomes with several types of cancers due to HA-driven support of adhesion, migration and proliferation of cells. In this study we explored how to enhance the degradation of HA into low-molecular fragments, which cannot prevent the immune system to fight tumor proliferation and metastases. The physiological solution of HA was exposed to oxidative degradation by ascorbate and cupric ions in the presence of either one of three ortho isomeric Mn(III) substituted N-alkyl- and alkoxyalkylpyridylporphyrins or para isomeric Mn(III) N-methylpyridyl analog, commonly known as mimics of superoxide dismutase. The changes in hyaluronan degradation kinetics by four Mn(III) porphyrins were monitored by measuring the alteration in the dynamic viscosity of the HA solution. The ortho compounds MnTE-2-PyP5+ (BMX-010, AEOL10113), MnTnBuOE-2-PyP5+ (BMX-001) and MnTnHex-2-PyP5+ are able to redox cycle with ascorbate whereby producing H2O2 which is subsequently coupled with Cu(I) to produce the •OH radical essential for HA degradation. Conversely, with the para analog, MnTM-4-PyP5+, no catalysis of HA degradation was demonstrated, due to its inertness towards redox cycling with ascorbate. The impact of different Mn(III)-porphyrins on the HA decay was further clarified by electron paramagnetic resonance spectrometry. The ability to catalyze the degradation of HA in a biological milieu, in the presence of cupric ions and ascorbate under the conditions of high tumor oxidative stress provides further insight into the anticancer potential of redox-active ortho isomeric Mn(III) porphyrins.

The Role of Porphyrinoid Photosensitizers for Skin Wound Healing.

Microorganisms, usually bacteria and fungi, grow and spread in skin wounds, causing infections. These infections trigger the immune system and cause inflammation and tissue damage within the skin or wound, slowing down the healing process. The use of photodynamic therapy (PDT) to eradicate microorganisms has been regarded as a promising alternative to anti-infective therapies, such as those based on antibiotics, and more recently, is being considered for skin wound-healing, namely for infected wounds. Among the several molecules exploited as photosensitizers (PS), porphyrinoids exhibit suitable features for achieving those goals efficiently. The capability that these macrocycles display to generate reactive oxygen species (ROS) gives a significant contribution to the regenerative process. ROS are responsible for avoiding the development of infections by inactivating microorganisms such as bacteria but also by promoting cell proliferation through the activation of stem cells which regulates inflammatory factors and collagen remodeling. The PS can act solo or combined with several materials, such as polymers, hydrogels, nanotubes, or metal-organic frameworks (MOF), keeping both the microbial photoinactivation and healing/regenerative processes' effectiveness. This review highlights the developments on the combination of PDT approach and skin wound healing using natural and synthetic porphyrinoids, such as porphyrins, chlorins and phthalocyanines, as PS, as well as the prodrug 5-aminolevulinic acid (5-ALA), the natural precursor of protoporphyrin-IX (PP-IX).

Cationic Pyrrolidine/Pyrroline-Substituted Porphyrins as Efficient Photosensitizers against E. coli.

New porphyrin-pyrrolidine/pyrroline conjugates were prepared by revisiting 1,3-dipolar cycloaddition reactions between a porphyrinic azomethine ylide and a series of dipolarophiles. Cationic conjugates obtained by alkylation of the pyrrolidine/pyrroline cycloadducts showed ability to generate singlet oxygen and to produce iodine in presence of KI when irradiated with visible light. Some of the cationic derivatives showed photobactericidal properties towards a Gram-negative bioluminescent E. coli. In all cases, these features were significantly improved using KI as coadjutant, allowing, under the tested conditions, the photoinactivation of the bacterium until the detection limit of the method with a drastic reduction of the required photosensitizer concentration and irradiation time. The obtained results showed a high correlation between the ability of the cationic porphyrin derivative to produce singlet oxygen and iodine and its E. coli photoinactivation profile.

Unraveling the Photodynamic Activity of Cationic Benzoporphyrin-Based Photosensitizers against Bladder Cancer Cells.

In this study, we report the preparation of new mono-charged benzoporphyrin complexes by reaction of the appropriate neutral benzoporphyrin with (2,2'-bipyridine)dichloroplatinum(II) and of the analogs' derivatives synthesized through alkylation of the neutral scaffold with iodomethane. All derivatives were incorporated into polyvinylpyrrolidone (PVP) micelles. The ability of the resultant formulations to generate reactive oxygen species was evaluated, mainly the singlet oxygen formation. Then, the capability of the PVP formulations to act as photosensitizers against bladder cancer cells was assessed. Some of the studied formulations were the most active photosensitizers causing a decrease in HT-1376 cells' viability. This creates an avenue to further studies related to bladder cancer cells.

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.

An Insight into the Role of Non-Porphyrinoid Photosensitizers for Skin Wound Healing.

The concept behind photodynamic therapy (PDT) is being successfully applied in different biomedical contexts such as cancer diseases, inactivation of microorganisms and, more recently, to improve wound healing and tissue regeneration. The effectiveness of PDT in skin treatments is associated with the role of reactive oxygen species (ROS) produced by a photosensitizer (PS), which acts as a "double agent". The release of ROS must be high enough to prevent microbial growth and, simultaneously, to accelerate the immune system response by recruiting important regenerative agents to the wound site. The growing interest in this subject is reflected by the increasing number of studies concerning the optimization of relevant experimental parameters for wound healing via PDT, namely, light features, the structure and concentration of the PS, and the wound type and location. Considering the importance of developing PSs with suitable features for this emergent topic concerning skin wound healing, in this review, a special focus on the achievements attained for each PS class, namely, of the non-porphyrinoid type, is given.

Tetrapyrrolic Macrocycles: Synthesis, Functionalization and Applications 2018.

Natural and synthetic macrocycles like porphyrins, corroles and phthalocyanines are considered strong candidates to be used in different fields, such as catalysis, sensing, medicine, materials science, or in the development of advanced biomimetic models. All these applications are strongly dependent on the availability of compounds with adequate and specific structural features. This Special Issue has collected 13 contributions which consolidate and expand our knowledge on the application of these macrocycles in different fields accompanied by innovative synthetic methodologies to afford and to functionalize this type of compounds.

Azides and Porphyrinoids: Synthetic Approaches and Applications. Part 2-Azides, Phthalocyanines, Subphthalocyanines and Porphyrazines.

The reaction between organic azides and alkyne derivatives via the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) is an efficient strategy to combine phthalocyanines and analogues with different materials. As examples of such materials, it can be considered the following ones: graphene oxide, carbon nanotubes, silica nanoparticles, gold nanoparticles, and quantum dots. This approach is also being relevant to conjugate phthalocyanines with carbohydrates and to obtain new sophisticated molecules; in such way, new systems with significant potential applications become available. This review highlights recent developments on the synthesis of phthalocyanine, subphthalocyanine, and porphyrazine derivatives where CuAAC reactions are the key synthetic step.

Azides and Porphyrinoids: Synthetic Approaches and Applications. Part 1-Azides, Porphyrins and Corroles.

Azides and porphyrinoids (such as porphyrin and corrole macrocycles) can give rise to new derivatives with significant biological properties and as new materials' components. Significant synthetic approaches have been studied. A wide range of products (e.g., microporous organic networks, rotaxane and dendritic motifs, dendrimers as liquid crystals, as blood substitutes for transfusions and many others) can now be available and used for several medicinal and industrial purposes.

New Materials Based on Cationic Porphyrins Conjugated to Chitosan or Titanium Dioxide: Synthesis, Characterization and Antimicrobial Efficacy.

The post-functionalization of 5,10,15-tris(1-methylpyridinium-4-yl)-20-(pentafluorophenyl)porphyrin tri-iodide, known as a highly efficient photosensitizer (PS) for antimicrobial photodynamic therapy (aPDT), in the presence of 3- or 4-mercaptobenzoic acid, afforded two new tricationic porphyrins with adequate carboxylic pending groups to be immobilized on chitosan or titanium oxide. The structural characterization of the newly obtained materials confirmed the success of the porphyrin immobilization on the solid supports. The photophysical properties and the antimicrobial photodynamic efficacy of the non-immobilized porphyrins and of the new conjugates were evaluated. The results showed that the position of the carboxyl group in the mercapto units or the absence of these substituents in the porphyrin core could modulate the action of the photosensitizer towards the bioluminescent Gram-negative Escherichia coli bacterium. The antimicrobial activity was also influenced by the interaction between the photosensitizer and the type of support (chitosan or titanium dioxide). The new cationic porphyrins and some of the materials were shown to be very stable in PBS and effective in the photoinactivation of E. coli bacterium. The physicochemical properties of TiO2 allowed the interaction of the PS with its surface, increasing the absorption profile of TiO2, which enables the use of visible light, inactivating the bacteria more efficiently than the corresponding PS immobilized on chitosan.

Supramolecular Hybrid Material Based on Engineering Porphyrin Hosts for an Efficient Elimination of Lead(II) from Aquatic Medium.

Porphyrins show great promise for future purification demands. This is largely due to their unique features as host binding molecules that can be modified at the synthetic level, and largely improved by their incorporation into inorganic based materials. In this study, we assessed the efficacy of a hybrid material obtained from the immobilization of 5,10,15,20-tetrakis(pentafluorophenyl)-porphyrin on silica surface to remove Pb(II), Cu(II), Cd(II), and Zn(II) ions from water. The new organic-inorganic hybrid adsorbent was fully characterized by adequate techniques and the results show that the hybrid exhibits good chemical and thermal stability. From batch assays, it was evaluated how the efficacy of the hybrid was affected by the pH, contact time, initial metal concentration, and temperature. The adsorption kinetic and isotherms showed to fit the recent developed fractal-like pseudo-second-order model and Langmuir⁻Freundlich model respectively. The highest adsorption capacities for Pb(II), Cu(II), Cd(II), and Zn(II) ions were 187.36, 125.17, 82.45, and 56.23 mg g-1, respectively, at pH 6.0 and 25 °C. This study also shows that metal cations from real river water samples can be efficient removed in the presence of the new adsorbent material.

A Suitable Functionalization of Nitroindazoles with Triazolyl and Pyrazolyl Moieties via Cycloaddition Reactions.

The alkylation of a series of nitroindazole derivatives with 1,2-dibromoethane afforded the corresponding N-(2-bromoethyl)- and N-vinyl-nitro-1H-indazoles. The Cu(I)-catalysed azide- alkyne 1,3-dipolar cycloaddition was selected to substitute the nitroindazole core with 1,4-disubstituted triazole units after converting one of the N-(2-bromoethyl)nitroindazoles into the corresponding azide. The reactivity in 1,3-dipolar cycloaddition reactions with nitrile imines generated in situ from ethyl hydrazono-α-bromoglyoxylates was studied with nitroindazoles bearing a vinyl unit. The corresponding nitroindazole-pyrazoline derivatives were obtained in good to excellent yields.

Porphyrin-Oligopyridine Triads: Synthesis and Optical Properties.

The synthesis of two triads with two porphyrinyl units linked by oligopyridine derivatives and a new ß-functionalized porphyrin-dihydroazepine is described. One of the porphyrin-oligopyridine triads has a quinquepyridine unit connecting the porphyrins ß-pyrrolic positions, while the other one has an asymmetric quaterpyridine with one of the pyridines fused to the porphyrin. All compounds have fluorescence emission quantum yields in the range of meso-tetraphenylporphyrin (16-22%).

N-Confused Porphyrin Immobilized on Solid Supports: Synthesis and Metal Ions Sensing Efficacy.

In this work, the N-confused porphyrin 5,10,15,20-tetraphenyl-2-aza-21-carbaporphyrin (NCTPP) was immobilized on neutral or cationic supports based on silica and on Merrifield resin. The new materials were characterized by appropriate techniques (UV-Vis spectroscopy, SEM, and zeta potential analysis). Piezoelectric quartz crystal gold electrodes were coated with the different hybrids and their ability to interact with heavy metals was evaluated. The preliminary results obtained showed that the new materials can be explored for metal cations detection and the modification of the material surface is a key factor in tuning the metal selectivity.

ß-Formyl- and ß-Vinylporphyrins: Magic Building Blocks for Novel Porphyrin Derivatives.

Porphyrins bearing formyl or vinyl groups have been explored as starting materials to prepare new compounds with adequate features for different applications. In this review it is discussed mainly synthetic strategies based on the reaction of meso-tetraarylporphyrins bearing those groups at ß-pyrrolic positions. The use of some of the obtained porphyrin derivatives for further transformations, namely via pericyclic reactions, is also highlighted.

A new 3,5-bisporphyrinylpyridine derivative as a fluorescent ratiometric probe for zinc ions.

A new 3,5-disubstituted pyridine with two porphyrin moieties was prepared through an efficient synthetic approach involving 2-formyl-5,10,15,20-tetraphenylporphyrin (1), piperidine, and catalytic amounts of [La(OTf)3]. 3,5-Bis(5,10,15,20-tetraphenylporphyrin-2-ylmethyl)pyridine (2) was fully characterized and its sensing ability towards Zn(2+), Cu(2+), Hg(2+), Cd(2+), and Ag(+) was evaluated in solution by absorption and fluorescence spectroscopy and in gas phase by using matrix-assisted laser desorption/ionization (MALDI)-TOF mass spectrometry. Strong changes in the ground and excited state were detected in the case of the soft metal ions Zn(2+), Cd(2+), Hg(2+), and Cu(2+). A three-metal-per-ligand molar ratio was obtained in all cases and a significant ratiometric behavior was observed in the presence of Zn(2+) with the appearance of a new band at 608 nm, which can be assigned to a metal-to-ligand charge transfer. The system was able to quantify 79 ppb of Zn(2+) and the theoretical calculations are in accordance with the stoichiometry observed in solution. The gas-phase sensorial ability of compound 2 towards all metal ions was confirmed by using MALDI-TOF MS and in solid state by using polymeric films of polymethylmethacrylate (PMMA) doped with ligand 2. The results showed that compound 2 can be analytically used to develop new colorimetric molecular devices that are able to discriminate between Hg(2+) and Zn(2+) in solid phase. The crystal structure of Zn(II) complex of 3,5-bisporphyrinylpyridine was unequivocally elucidated by using single-crystal X-ray diffraction studies.