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Meso -tetra-(4-pyridyl)porphyrin/Palladium(II) Complexes as Anticancer Agents
Abstract
This study reports on the synthesis, structural characterization and cytotoxic activity of four new Palladium/pyridylporphyrin complexes, with general formula {TPyP[PdCl(P-P)] 4 }(PF 6 ) 4 , where P-P are the 1,2-bis(diphenylphosphino)ethane (dppe), 1,3-bis(diphenylphosphino)propane (dppp), 1,2-bis(diphenylphosphino)butane (dppb)...
Metal complexes have a significant impact on the treatment of human cancer. However, the scarcity of these compounds, resulting from their limited synthesis, hinders the comprehensive investigation of their anticancer mechanisms. Organic palladium compounds, known for their distinctive stability and properties, are thus an essential area of research in the development of anti‐tumor therapy. In our study, we synthesized two novel ferrocene cyclopalladated compounds ( C2 and C4 ). Its configuration was thoroughly characterized by employing ¹ H, ¹³ C NMR, ESI‐MS, and elemental analysis techniques. The molecular structures were determined by X‐ray single‐crystal diffraction. In an in vitro anticancer study, it was observed that both C2 and C4 exhibited excellent suppression of viability in various tumor cell lines. These compounds showed better potency than cisplatin and demonstrated lower toxicity in normal cells. Particularly, C4 displayed approximately 22 times greater potency than cisplatin in suppressing melanoma cells (B16F10). Our study suggests that ferrocene cyclopalladated compounds have the potential to be promising candidates for the development of innovative anticancer drugs.
Palladium(II) complexes have stimulated the research interest mainly due to their in vitro cytotoxicity against various cancer cell lines, and their low cytotoxicity in healthy cells. Thus, in this work,...
Porphyrins feature prominently in nature, be it as enzymatic cofactors, electron and exciton shuffles, as photoactive dyes, or as signaling substances. Their involvement in the generation, storage and use of oxygen is pivotal to life, while their photochemical properties are central to the biochemical functioning of plants. When complexed to metals, porphyrins can engage in a multitude of contemporary applications ranging from solar energy generation to serving as catalysts for important chemical reactions. They are also able to function as useful theranostic agents, and as novel materials for a wide range of applications. As such, they are widely considered to be highly valuable molecules, and it almost goes without saying that synthetic organic chemistry has dramatically underpinned all the key advances made, by providing reliable access to them. In fact, strategies for the synthesis of functionalized porphyrins have now reached a state of refinement where pretty well any desired porphyrin can successfully be synthesized with the approaches that are available, including a cornucopia of related macrocycle-modified porphyrinoids. In this review, we are going to illustrate the development of this exciting field by discussing a number of classic syntheses of porphyrins. Our coverage will encompass the natural protoporphyrins and chlorophylls, while also covering general strategies for the synthesis of unsymmetrical porphyrins and chlorins. Various industrial syntheses of porphyrins will also be discussed, as will other routes of great practical importance, and avenues to key porphyrinoids with modified macrocycles. A range of selected examples of contemporary functionalization reactions will be highlighted. The various key syntheses will be described and analyzed from a traditional mechanistic organic chemistry perspective to help student readers, and those who are new to this area. The aim will be to allow readers to mechanistically appreciate and understand how many of these fascinating ring-systems are built and further functionalized.
Porphyrins are macrocyclic tetrapyrrole derivatives that are widely distributed in nature. They are often complexed with a metal ion located in the center of the ring system and may be modified by various substituents including additional rings, or by ring opening, which leads to a plethora of different functions. Due to their extended conjugated aromatic ring system, porphyrins absorb light in the visible range and therefore show characteristic colors. Well-known natural porphyrins include the red-colored heme present in hemoglobin, which is responsible for blood oxygen transport, and the chlorophylls in some bacteria and in plants which are utilized for photosynthesis. Porphyrins are mostly lipophilic pigments that display relatively high chemical stability. Therefore, they can even survive hundreds of millions of years. The present review article provides an overview of natural porphyrins, their chemical structures, and properties. A special focus is put on porphyrins discovered in the fossil record. Examples will be highlighted, and information on their chemical analysis will be provided. We anticipate that the development of novel analytical methods with increased sensitivity will prompt new discoveries of porphyrins in fossils.
The program Mercury , developed at the Cambridge Crystallographic Data Centre, was originally designed primarily as a crystal structure visualization tool. Over the years the fields and scientific communities of chemical crystallography and crystal engineering have developed to require more advanced structural analysis software. Mercury has evolved alongside these scientific communities and is now a powerful analysis, design and prediction platform which goes a lot further than simple structure visualization.
Intermolecular interactions of organic, inorganic, and organometallic compounds are the key to many composition–structure and structure–property networks. In this review, some of these relations and the tools developed by the Cambridge Crystallographic Data Center (CCDC) to analyze them and design solid forms with desired properties are described. The potential of studies supported by the Cambridge Structural Database (CSD)-Materials tools for investigation of dynamic processes in crystals, for analysis of biologically active, high energy, optical, (electro)conductive, and other functional crystalline materials, and for the prediction of novel solid forms (polymorphs, co-crystals, solvates) are discussed. Besides, some unusual applications, the potential for further development and limitations of the CCDC software are reported.
The efficacy of organoruthenium complexes containing ergosterol biosynthesis inhibitors (CTZ: clotrimazole, KTZ: ketoconazole and FCZ: fluconazole) against tumor cells, and their interaction with important macro-biomolecules such as human serum albumin and DNA have been investigated here. Our experimental results indicated that these ruthenium(II) complexes present spontaneous electrostatic interactions with albumin, and act as minor groove binders with the DNA. The ability of these Ru(II)–azole complexes to inhibit the proliferation of selected human tumor and non-tumor cell lines was determined by MTT assay. Complexes [RuCl(CTZ)(η6-p-cymene)(PPh3)]PF6 (3) and [RuCl(KTZ)(η6-p-cymene)(PPh3)]PF6 (4) were shown to be between 3- and 40-fold more cytotoxic than the free ligands and the positive control cisplatin. Complex 3 was selected to continue studies on the triple negative breast tumor cell line MDA-MB-231, inducing morphological changes, loss of adhesion, inhibition of colony formation, and migration through Boyden chambers, cell cycle arrest in the sub-G1 phase, and a mechanism of cell death by apoptosis. All these interesting results show the potential of this class of organometallic Ru(II) complexes as an antiproliferative agent.
Brain cancers, is a fatal disease that is difficult to treat because of poor targeting and low permeability of chemotherapeutic drugs through the blood brain barrier. Compared to current treatments, such as surgery followed by chemotherapy and/or radiotherapy, photothermal therapy is as a remarkable non-invasive therapy developed in recent years. In this work, porphyrin immobilized nano-graphene oxide (PNG) was synthesized and bioconjugated with a peptide to achieve enhanced and targeted photothermal therapy for brain cancer. PNG was dispersed into the agar based artificial tissue model and demonstrated a photo-to-thermal conversion efficiency of 19.93% at a PNG concentration of only 0.5wt%, with a heating rate of 0.6ºC/second at the beginning of irradiation. In comparison, 0.5 wt% graphene oxide (GO) indicated a photo-to-thermal conversion efficiency of 12.20% and a heating rate of 0.3ºC/second. To actively target brain tumor cells without harming healthy cells and tissues surrounding the laser path, a tripeptide L-Arginyl-Glycyl-L-Aspartic (RGD) was further grafted to PNG. The photothermal therapy effects of PNG-RGD completely eliminated the tumor in-vivo, indicating its excellent therapeutic effect for the treatment of brain cancer.
G-quadruplexes are non-canonical DNA structures formed by guanine-rich DNA sequences that are implicated in cancer and aging. Understanding how small molecule ligands interact with quadruplexes is essential both to the development of novel anticancer therapeutics and to the design of new quadruplex-selective probes needed for elucidation of quadruplex biological functions. In this work, UV–visible, fluorescence, and circular dichroism spectroscopies, fluorescence resonance energy transfer (FRET) melting assays, and resonance light scattering were used to investigate how the Pt(II) and Pd(II) derivatives of the well-studied 5,10,15,20-tetrakis(N-methyl-4-pyridyl)porphyrin (TMPyP4) interact with quadruplexes formed by the human telomeric DNA, Tel22, and by the G-rich sequences from oncogene promoters. Our results suggest that Pt- and PdTMPyP4 interact with Tel22 via efficient π–π stacking with a binding affinity of 106–107 M−1. Under porphyrin excess, PtTMPyP4 aggregates using Tel22 as a template; the aggregates reach maximum size at [PtTMPyP4]/[Tel22] ~8 and dissolve at [PtTMPyP4]/[Tel22] ≤ 2. FRET assays reveal that both porphyrins are excellent stabilizers of human telomeric DNA, with stabilization temperature of 30.7 ± 0.6 °C for PtTMPyP4 and 30.9 ± 0.4 °C for PdTMPyP4 at [PtTMPyP4]/[Tel22] = 2 in K+ buffer, values significantly higher as compared to those for TMPyP4. The porphyrins display modest selectivity for quadruplex vs. duplex DNA, with selectivity ratios of 150 and 330 for Pt- and PdTMPyP4, respectively. This selectivity was confirmed by observed ‘light switch’ effect: fluorescence of PtTMPyP4 increases significantly in the presence of a variety of DNA secondary structures, yet the strongest effect is produced by quadruplex DNA.
Graphical abstract
Tetrapyrrole-containing proteins are one of the most fundamental classes of enzymes in nature and it remains an open question to give a chemical rationale for the multitude of biological reactions that can be catalyzed by these pigment-protein complexes. There are many fundamental processes where the same (i.e., chemically identical) porphyrin cofactor is involved in chemically quite distinct reactions. For example, heme is the active cofactor for oxygen transport and storage (hemoglobin, myoglobin) and for the incorporation of molecular oxygen in organic substrates (cytochrome P450). It is involved in the terminal oxidation (cytochrome c oxidase) and the metabolism of H2O2 (catalases and peroxidases) and catalyzes various electron transfer reactions in cytochromes. Likewise, in photosynthesis the same chlorophyll cofactor may function as a reaction center pigment (charge separation) or as an accessory pigment (exciton transfer) in light harvesting complexes (e.g., chlorophyll a). Whilst differences in the apoprotein sequences alone cannot explain the often drastic differences in physicochemical properties encountered for the same cofactor in diverse protein complexes, a critical factor for all biological functions must be the close structural interplay between bound cofactors and the respective apoprotein in addition to factors such as hydrogen bonding or electronic effects. Here, we explore how nature can use the same chemical molecule as a cofactor for chemically distinct reactions using the concept of conformational flexibility of tetrapyrroles. The multifaceted roles of tetrapyrroles are discussed in the context of the current knowledge on distorted porphyrins. Contemporary analytical methods now allow a more quantitative look at cofactors in protein complexes and the development of the field is illustrated by case studies on hemeproteins and photosynthetic complexes. Specific tetrapyrrole conformations are now used to prepare bioengineered designer proteins with specific catalytic or photochemical properties.
Isatin and 1H-1,2,3-triazoles are two classes of compounds with great prominence in organic synthesis and medicinal chemistry as they are heterocycle nuclei with a high reactivity allowing to obtain several compounds with important biological properties. Herein, the synthesis of novel 5'-(4-alquil/aril-1H-1,2,3-triazole)-isatin via reaction of 1,3-dipolar cycloaddition catalyzed by acetic acid is reported.
Increasing numbers of DNA structures are being revealed using biophysical, spectroscopic and genomic methods. The diversity of transition metal complexes is also growing, as the unique contributions that transition metals bring to the overall structure of metal complexes depend on the various coordination numbers, geometries, physiologically relevant redox potentials, as well as kinetic and thermodynamic characteristics. The vast range of ligands that can be utilised must also be considered. Given this diversity, a variety of biological interactions is not unexpected. Specifically, interactions with negatively-charged DNA can arise due to covalent/coordinate or subtle non-coordinate interactions such as electrostatic attraction, groove binding and intercalation as well as combinations of all of these modes. The potential of metal complexes as therapeutic agents is but one aspect of their utility. Complexes, both new and old, are currently being utilised in conjunction with spectroscopic and biological techniques to probe the interactions of DNA and its many structural forms. Here we present a review of metal complex-DNA interactions in which several binding modes and DNA structural forms are explored.
Photodynamic activity of chloro(5,10,15,20-tetraphenylporphyrinato)indium(III) (InTPP) in vitro was investigated for possible use in photodynamic therapy (PDT). The quantum yield of singlet oxygen generation in DMSO of InTPP (FD = 0.72) was higher than 5,10,15,20-tetraphenylporphyrin (TPP) (FD = 0.52). Binding sites between photosensitizers and bovine serum albumin (BSA) are independent while binding sites with human red blood cells (RBC) are cooperatives, with one and four binding sites per molecule, respectively. Binding constants with BSA are (1.15 ± 0.07) × 105 and (2.6 ± 0.1) × 104 L mol-1 and with RBC are (2.40 ± 0.05) × 107 L mol-1 e (7.2 ± 0.2) × 104 L mol-1 for InTPP and Photofrin®, respectively. InTPP was more efficient than Photofrin® in the photooxidation of L-tryptophan(Trp) and BSA when higher concentrations (14 µmol L1) of photosensitizers were used. InTPP was 1.37-1.5 times more effective in the photooxidation of RBC than Photofrin®. Our results indicate that InTPP should be used in future studies of PDT.
This work employs the Z -scan technique with 120 fs pulses to investigate the singlet excited state absorption spectra of tetrapyridyl and tetrasulfonatophenyl porphyrins. We have used a three-energy-level model to adjust Z -scan curves in order to obtain the singlet excited absorption cross section from 460 to 800 nm . Starting from these values, we determine the spectra of the ratio between excited and ground singlet state absorption cross sections, whose values are as good as the best found in the literature for reverse saturable absorbers. The results obtained point these porphyrins as good candidates for applications in optical limiting of ultrashort pulses.
In this study, a new fluorinated phthalonitrile compound namely 5-bis[4-(trifluoromethoxy)-thiophenyl] phthalonitrile was synthesized. In addition, peripherally substituted symmetric metallated phthalocyanine derivatives [M = Co (2) and M = Zn (3)] and unsymmetrically substituted zinc phthalocyanine (ZnPc) complex (4) were synthesized by cyclotetramerization of this phthalonitrile compound. Characterization of all new compounds was carried out using FT-IR, NMR, UV-Vis, and mass spectroscopy. Additionally, antioxidant activity, DNA cleavage activity, antimicrobial activity, biofilm inhibition activity, and bacterial viability inhibition test of the compounds (1-4) were investigated. The antioxidant activities of the new phthalocyanine complexes were studied by performing two different methods. The results indicated that the highest DPPH (1,1-diphenyl-2-picrylhydrazyl) free radical scavenging activity was determined to be 67.85% for 2 and also 3 showed the highest activity with 31.65% for chelating activity at 200 mg L-1 concentration. Phthalocyanine compounds demonstrated effective DNA cleavage and antimicrobial activities. The highest percentage of cell vitality inhibition was found for compound 4, 56.92%. Also, test compounds exhibited good biofilm inhibition activity.
The present work reports the spectroscopic and theoretical evaluation of the interaction between calf-thymus DNA (CT-DNA) and free-base meso-tetra-(ruthenated) porphyrin (H2RuTPyP) or its corresponding Zn(II) complex (ZnRuTPyP). Spectroscopic measurements (UV–vis, circular dichroism and steady-state fluorescence emission) combined with theoretical molecular docking calculations suggest that Ru(II)-porphyrins interact with the DNA backbone by external mode via electrostatic forces. In addition, gel electrophoresis analysis demonstrate that these porphyrins promote efficient plasmidial DNA photocleavage upon white-light irradiation conditions, indicating H2RuTPyP and ZnRuTPyP as potential candidates for photodynamic therapy.
In this work, we first report the antimicrobial photoinactivation using tetra-cationic porphyrins with peripheral palladium(II) complexes against bacterial strains. Two different isomeric Pd(II)-porphyrins were used and applied in PDI experiments in the strains Gram negative bacilli Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa and a Gram positive cocci Staphylococcus aureus. All experiments are conducted with adequate concentration (without aggregation) of photosensitizer under white-light irradiation over 2 h showed that the most effective PS caused a significative reduction in the concentration of viable bacteria. The present results show that porphyrin with positively charge at meta position (3-PtTPyP) are more efficient photosensitizer against bacteria strains. In this way, tetra-cationic porphyrins might be promising antibacterial PDI agents with potential applications in medical clinical cases.
New isomeric tetra-cationic porphyrins containing peripheral [Pd(bpy)Cl]+ units attached at pyridyl substituents were synthetized and fully characterized. The porphyrins present an intense Soret band located in the blue spectral region and additional four weaker red-shifted Q bands in the visible spectral region (about 500-700 nm). The obtained Strickler-Berg parameters indicate fully spin and symmetry allowed transitions for all the observed absorption bands. Both porphyrins present two fluorescence emission bands, an intense one located around 650 nm with an additional weak red-shifted emission at ~710 nm. Fluorescence decay time profiles were obtained showing bi-exponential decay. The interaction of the porphyrins with bovine serum albumin (BSA) was studied in detail by fluorescence quenching method and molecular docking analysis. In addition, the photodynamical activity of the porphyrins in photo-oxidation of BSA was determined and compared with the light-induced formation of reactive oxygen species (ROS) by electron paramagnetic resonance (EPR) allied with the spin trapping method. The results show that the Pd(II)-bypiridyl tetra-caticonic porphyrins are promising candidates in photo-oxidation processes of biological substrates used in photodynamical therapy (PDT).
Six new ruthenium(II) complexes with lapachol (Lap) and lawsone (Law) with the general formula [Ru(L)(P-P)(bipy)]PF6, where L = Lap or Law, P-P = 1,2’-bis(diphenylphosphino)ethane (dppe), 1,4’-bis(diphenylphosphino)butane (dppb), 1,1’-bis(diphenylphosphino)ferrocene (dppf) and bipy = 2,2’-bipyridine, were synthesized, fully characterized by elemental analysis, molar conductivity, NMR, cyclic voltammetry, UV-vis, IR spectroscopies and three of them by X-ray crystallography. All six complexes were active against breast (MCF-7 and MDA-MB-231) and prostate (DU-145) cancer cell lines with lower IC50 values than cisplatin. Complex [Ru(Lap)(dppe)(bipy)]PF6 (1a) showed significant selectivity for MDA-MB-231, a model of triple-negative breast cancer (TNBC), as compared to the “normal-like” human breast epithelial cell line, MCF-10A. Complex (1a) inhibited TNBC colony formation, induced loss of cellular adhesion. Furthermore, the complex (1a) induced mitochondrial dysfunction and generation of ROS, what is involved in the apoptotic cell death pathway. Preferential cellular uptake of complex (1a) was observed in MDA-MB-231 cells compared to MCF-10A cells, consistent with the observed selectivity for tumorigenic vs non-tumorigenic cells. Taken together, these results indicate that ruthenium complexes containing lapachol and lawsone as ligand are promising candidates as chemotherapeutic agents.
In this work, we present the synthesis and characterization of five new ruthenium compounds with general formula [Ru(L)(dppb)(bipy)]PF6, where L = cinnamic acid derivatives, dppb = 1,4-bis(diphenylphosphino)butane and bipy = 2,2'-bipyridine. The cytotoxicity of the complexes was evaluated against human breast tumor cells from the lines MCF-7, MDA-MB-231 and in human (MCF-10A) or mouse (L929) non-tumor cells. Complexes Ru(L4)(dppb)(bipy)]PF6 (4) (L4 = 4-hydroxycinnamic acid) and [Ru(L5)(dppb)(bipy)]PF6 (5) (L5 = 3,4-dihydroxycinnamic acid) were the most selective, presenting the highest values of selectivity indexes besides inhibited some processes related to tumor progression in vitro, such as invasion, migration, and adhesion in the MDA-MB-231 cell line. In addition, the complexes 4 and 5 were able to interact with Bovine Serum Albumin (BSA) and complex 5 showed antioxidant activity.
In the present scenario, promising efforts have been improved by the researchers towards the development of nanocarriers that can be challenge fundamental tasks in photodynamic therapy (PDT) for wound management. In the past few years, nanotechnology-based therapy has attracted good attention with the advancement of nanotechnology such as PDT, chemotherapy, photothermal therapy. PDT has emerged as a promising clinical treatment method for wound healing. In this respect, great effort has been made towards the development of nanocarriers for targeted PDT in wound management. Nowadays, attention is concentrated on the advancement of nanomaterials using innovative methods in wound care for treating wounds with the faster healing effect. In this review, we present and discuss how nanocarriers have arisen as an interesting delivery nanoplatform for effective and consistent PDT. They can be easily delivered photodynamically and can demonstrate healing mechanisms for achieving target wound tissue/cells; therefore, PDT can be used in wound treatment to target cells specifically through release on demand, target-specific delivery, and in vivo labelling imaging. In addition, we also highlighted that the future goal for researchers is the development of biocompatible and biodegradable nanomaterials for all the phases of wound healing.
In this study, we report on the selective esterification of the carboxyl group in a coordinated ligand based on the Fischer reaction. The new [Ru(N-O)(bipy)(dppb)]PF6 complex 1 was used as a precursor to obtain the ester derivative [Ru(N-Oet)(bipy)(dppb)]PF6 (2), and in order to establish the influence of either free carboxyl or ethoxycarbonyl group on biological properties, the [Ru(pic)(bipy)(dppb)]PF6 complex (3) was synthetized for comparison (dppb = 1,4-bis(diphenylphosphino)butane, bipy = 2,2’-bipyridine, N-O = mono-deprotonated 2,4-pyridinedicarboxylic acid, N-Oet = 4-ethoxycarbonyl-2-pyridinecicarboxylic acid). All three complexes interact weakly with human serum albumin (HSA) with Kb values ranging from 10¹–10⁴ M⁻¹, suggesting a spontaneous interaction with this protein, by electrostatic (1 - 2) or van der Walls interactions (3). Moreover, complex/DNA-binding experiments indicate that complexes 2 and 3 interact weakly with DNA, while no interaction is observed between complex 1 and DNA, probably due to the repulsion involving the free carboxylate group/DNA-phosphate. Anti-Mycobacterium tuberculosis (MTB) activity, cytotoxicity assays against one normal cell line V79 (hamster fibroblast) and three human cancer cells as A549 (lung), MCF7 and MDA-MB-231 (breast), revealed that complexes 2 and 3 exhibit good activity against MTB and tumor cells, presenting high cytotoxicity (low IC50). On the other hand, complex 1 is practically inactive. Therefore, the best biological results found for complex 2 can be attributed to its esterification, improving the lipophilicity and cellular uptake, in order to facilitate its passive permeation through the tumor cell membranes allowing for cell death, as well as DNA and HSA interactions, when compared with complex 1.
Complexes derived from meso-tetra(thienyl)porphyrins (TThP) and meso-tetra(pyridyl)porphyrin (TPyP) containing peripheral ruthenium complexes with general formulas {TPyP[RuCl(dppb)(5,5′-Mebipy)]4}(PF6)4, {TThP[RuCl(dppb)(5,5′-Mebipy)]4}(PF6)4, and {TThP-me-[RuCl(dppb)(5,5′-Mebipy)]4}(PF6)4 [5,5′-Mebipy = 5,5′-dimethyl-2,2′-bipyridine and dppb = 1,4-bis(diphenylphosphino)butane] were synthesized and characterized by spectroscopy techniques (¹H- and ³¹P{¹H}-NMR, IR, UV/vis, fluorescence, and electron paramagnetic resonance (EPR)), cyclic voltammetry, coulometry, molar conductivity, and elemental analysis. Voltammetry and UV/vis studies demonstrated differentiated electronic properties for ruthenium appended with TThP and TThP-me when compared to ruthenium appended with TPyP. The UV/vis analysis for the ruthenium complex derived from TThP and TThP-me, as well as the Soret and Q bands, characteristics of porphyrins, showed a band at 700 nm referring to the Ru → S electronic transition, and porphyrin TThP-me showed another band at 475 nm from the Ru-N transition. The attribution of these bands was confirmed by spectroelectrochemical analysis. Cyclic voltammetry analysis for the ruthenium complex derived from TPyP exhibited only an electrochemical process with E1/2 = 0.47 V assigned to the Ru(II)/Ru(III) redox pair (Fc/Fc⁺). On the other hand, two processes were observed for the ruthenium complexes derived from TThP and TThP-me, with E1/2 around 0.17 and 0.47 V, which were attributed to the formation of a mixed valence tetranuclear species containing Ru(II) and Ru(III) ions, showing that the peripheral groups are not oxidized at the same potential. Fluorescence spectroscopic experiments show the existence of a mixed state of emission in the supramolecular porphyrin moieties. The results suggest the formation of Ru(II)-Ru(III) mixed valence complexes when oxidation potential was applied around 0.17 V in the {TThP[RuCl(dppb)(5,5′-Mebipy)]4}(PF6)4 and {TThP-me-[RuCl(dppb)(5,5′-Mebipy)]4}(PF6)4 species.
Porphyrins are organic heterocyclic macrocycles with photophysical properties well-suited for clinical phototherapy and cancer imaging. However, their wider application in the clinical management of disease is barred by poor aqueous solubility, bioavailability, tumour accumulation and skin phototoxicity. These limitations instigated the development of supramolecular platforms that improved porphyrin pharmacokinetics and tumour-homing. The supramolecular formulation of porphyrins also facilitates single agent-mediated deeper tissue photoactivation, extended imaging and theranostic multimodality, and synergistic application of multiple therapies. Supramolecular porphyrin structures can overcome additional limitations of porphyrin-mediated photodynamic therapy (PDT), including low depths of tissue penetration that restrict PDT to superficial lesions, inability to treat hypoxic tumours, and incomplete tumour damage. In this review, we discuss the photophysical properties of porphyrins, and overview the clinically-relevant advantages and challenges arising from their incorporation within supramolecular platforms. Specifically, fundamentals underlying the ability of these platforms to ameliorate passive and active porphyrin delivery to tumours, achieve deeper tissue PDT via red-shifted porphyrin Q-bands, energy transfer and sonodynamic effects, and enable new porphyrin-mediated theranostics and synergistic therapeutic capabilities will be explained and exemplified with seminal and cutting-edge in vivo studies.
The new complexes of Pd(II) with N,N-disubstituted-N′-acylthioureas:[(1) [Pd(dppf)(N,N-dimethyl-N′-benzoylthioureato-k²O,S)]PF6, (2) [Pd(dppf)(N,N-diethyl-N′-benzoylthioureato-k²O,S)]PF6, (3) [Pd(dppf)(N,N-dibuthyl-N′-benzoylthioureato-k²O,S)]PF6, (4) [Pd(dppf)(N,N-diphenyl-N′-benzoylthioureato-k²O,S)]PF6, (5) [Pd(dppf)(N,N-diethyl-N′-furoylthioureato-k²O,S)]PF6, (6) [Pd(dppf)(N,N-diphenyl-N′-furoylthioureato-k²O,S)]PF6, (7) [Pd(dppf)(N,N-dimethyl-N′- thiophenylthioureato-k²O,S)]PF6, and (8) [Pd(dppf)(N,N-diphenyl-N′-thiophenylthioureato-k²O,S)]PF6, were prepared and characterized by elemental analysis, and spectroscopic techniques. The structures of complexes (2), (3), (5), (6) and (8) had their structures determined by X-ray crystallography, confirming the coordination of the ligands with the metal through sulfur and oxygen atoms, forming distorted square-planar geometries. These complexes have shown antibacterial activity against Anti-M. tuberculosis H37Rv ATCC 27294. The complexes exhibited antiparasitic activity against T. cruzi, while the metal-free thioureas did not. The results demonstrated that the compounds described here can be considered as promising anti-M. tuberculosis and anti-T. cruzi agents, since in both cases their in vitro activity were better than reference drugs available for the treatment of both diseases.
In this work, we evaluate the interaction of the peripheral Pt(bpy)Cl(+) substituted porphyrins, H2PtPor and ZnPtPor with DNA using UV-vis, emission fluorescence, CD spectroscopy, and DNA melting properties altered by the Pt(ii)-porphyrinoid compounds. Additionally, we observe the ability of these porphyrin derivatives to generate (1)O2 and to efficiently photocleave plasmid DNA upon visible light irradiation based on a mixed (oxidative/hydrolytic) mechanism.
The photosensitizers used in photodynamic therapy are mainly based on porphyrin derivatives. However, clinical applications encounter several limitations regarding photosensitizers such as their low absorption coefficients, poor water-solubility, and leaching from delivery carriers. Here, we describe covalent incorporation of porphyrin in conjugated polymer backbone for development of efficient polymer-dot photosensitizer. Spectroscopic characterizations revealed that the light-harvesting polymer dominantly transfer the excitation energy to the porphyrin unit, yielding efficient singlet oxygen generation for photodynamic therapy. The polymer dots also possess excellent stability that overcomes the photosensitizer leaching problem as encountered in other nanoparticle carriers. In vitro cytotoxicity and photodynamic efficacy of the Pdots were evaluated in MCF-7 cells by MTT assays, indicating that the Pdots can efficiently damage cancer cells. In vivo photodynamic therapy by using the Pdots was further investigated with xenograft tumors in Balb/c nude mice, which show that the tumors were significantly inhibited or eradicated in certain cases. The high-yield singlet oxygen generation and excellent stability of porphyrin-incorporated Pdots are promising for photodynamic treatment of malignant tumors.
Abstract This work presents the simultaneous determination of catechol (CC) and hydroquinone (HQ), employing a modified glassy carbon electrode with tetraruthenated oxovanadium (IV) porphyrin. The GCE was modified by electropolymerization of {VOTPyP[RuCl3(dppb)]4} porphyrin, onto the GCE surface, by cyclic voltammetry. The modified electrode, labeled as VOTPRu-GCE, showed two pairs of well-defined redox peaks for the electrochemical processes of catechol and hydroquinone. In bare GCE, the potential difference (ΔEp) of CC and HQ were 469 mV and 457 mV, respectively, while with VOTPRu-GCE the potential difference decreased to 29 mV and 30 mV, indicating that the redox processes were reversible onto the VOTPRu-GCE surface. With differential pulse voltammetry, it was possible to simultaneously determine the CC and HQ, with peak-to-peak potential separation of 129 mV, in 0.1 mol L-1 acetate buffer (pH 4.75). Under the optimized conditions, the calibration curves were obtained in the linear concentration ranges of 2-38 μmol L-1 for both isomers using the VOTPRu-GCE, which showed high sensitivity in the determination of CC and HQ, 12.73 and 15.91 μA μmol L-1 cm-2, respectively. The detection limits were 0.41 and 0.55 μmol L-1 for CC and HQ, respectively.
The use of glycosylated porphyrins, phthalocyanines, and other porphyrinoids for diagnostics and therapeutics are discussed. Porphyrins and phthalocyanines (Pcs) are the most common and efficient photosensitizers (PSs) used in photodynamic therapy (PDT) due to their absorption in the visible range of the electromagnetic spectrum, long-lived triplet excited state, and efficient phototoxicity toward cancer cells. Several derivatives can be prepared from porphyrins and phthalocyanines because of the stability of the core macrocycle. New methods have been developed to synthesize dihydroporphyrins and tetrahydroporphyrins for diagnostics and therapeutics uses.
The synthesis and spectroscopic characterization of nine π-arene piano-stool ruthenium (II) complexes with aromatic dinitrogen chelating ligands or containing chloroquine (CQ), are described in this study: [Ru(η(6)-C10H14)(phen)Cl]PF6 (1), [Ru(η(6)-C10H14)(dphphen)Cl]PF6 (2), [Ru(η(6)-C10H14)(bipy)Cl]PF6 (3), [Ru(η(6)-C10H14)(dmebipy)Cl]PF6 (4) and [Ru(η(6)-C10H14)(bdutbipy)Cl]PF6 (5), [Ru(η(6)-C10H14)(phen)CQ](PF6)2 (6), [Ru(η(6)-C10H14)(dphphen)CQ](PF6)2 (7), [Ru(η(6)-C10H14)(bipy)CQ](PF6)2 (8), [Ru(η(6)-C10H14)(dmebipy)CQ](PF6)2 (9): [1,10-phenanthroline (phen), 4,7-diphenyl-1,10-phenanthroline (dphphen), 2,2'-bipyridine (bipy), 5,5'-dimethyl-2,2'-bipyridine (dmebipy), and 4,4'-di-t-butyl-2,2'-bipyridine (dbutbipy)]. The solid state structures of five ruthenium complexes (1-5) were determined by X-ray crystallography. Electrochemical experiments were performed by cyclic voltammetry to estimate the redox potential of the Ru(II)/Ru(III) couple in each case. Their interactions with DNA and BSA, and activity against four cell lines (L929, A549, MDA-MB-231 and MCF-7) were evaluated. Compounds 2, 6 through 9, interact with DNA which was comparable to the one observed for free chloroquine. The results of fluorescence titration revealed that these complexes strongly quenched the intrinsic fluorescence of BSA following a static quenching procedure. Binding constants (Kb) and the number of binding sites (n~1) were calculated using modified Stern-Volmer equations. The thermodynamic parameters ΔG at different temperatures were calculated and subsequently the values of ΔH and ΔS were also calculated, which revealed that hydrophobic and electrostatic interactions play a major role in the BSA-complex association. The MTT assay results indicated that complexes 2, 5 and 7 showed cytostatic effects at appreciably lower concentrations than those needed for cisplatin, chloroquine and doxorubicin.
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Four ruthenium(II)-based complexes with N-(acyl)-N',N'-(disubstituted)thiourea derivatives (Th) were obtained. The compounds, with the general formula trans-[Ru(PPh3)2(Th)(bipy)]PF6, interact with bovine serum albumin (BSA) and DNA. BSA-binding constants, which were in the range of 3.3-6.5×10(4)M(-1), and the thermodynamic parameters (ΔG, ΔH and ΔS), suggest spontaneous interactions with this protein by electrostatic forces due to the positive charge of the complexes. Also, binding constant by spectrophotometric DNA titration (Kb=0.8-1.8×10(4)M(-1)) and viscosity studies indicate weak interactions between the complexes and DNA. Cytotoxicity assays against DU-145 (prostate cancer) and A549 (lung cancer) tumour cells revealed that the complexes are more active in tumour cells than in normal (L929) cells, and that they present high cytotoxicity (low IC50 values) compared with the reference metallodrug, cisplatin.
Copyright © 2015. Published by Elsevier Inc.
Porphyrins and other tetrapyrrole macrocycles possess an impressive variety of functional properties that have been exploited in natural and artificial systems. Different metal centres incorporated within the tetradentate ligand are key for achieving and regulating vital processes, including reversible axial ligation of adducts, electron transfer, light-harvesting and catalytic transformations. Tailored substituents optimize their performance, dictating their arrangement in specific environments and mediating the assembly of molecular nanoarchitectures. Here we review the current understanding of these species at well-defined interfaces, disclosing exquisite insights into their structural and chemical properties, and also discussing methods by which to manipulate their intramolecular and organizational features. The distinct characteristics arising from the interfacial confinement offer intriguing prospects for molecular science and advanced materials. We assess the role of surface interactions with respect to electronic and physicochemical characteristics, and describe in situ metallation pathways, molecular magnetism, rotation and switching. The engineering of nanostructures, organized layers, interfacial hybrid and bio-inspired systems is also addressed.
Among the several approaches for harnessing solar energy and converting it into electricity, dye-sensitized solar cells (DSSC) represent one of the most promising methods for future large-scale power production from renewable energy sources. In these cells, the sensitizer is one of the key components harvesting solar radiation and converting it into electric current. The electrochemical, photophysical, and ground and excited state properties of the sensitizer play an important role for charge transfer dynamics at the semiconductor interface. Moreover, for long-term stability and practical applications, electrolytes based on the iodine/triiodine couple also suffer from two other disadvantages: the corrosive effect toward the metal electrodes, and the partial absorption of the visible light by triiodine anions. These issues hence constitute one of the reasons that have encouraged the development of alternative iodine-free redox couples in liquid electrolytes for DSSCs.
This review presents comprehensively recent progress in metal-metalloporphyrin frameworks (MMPFs) with an emphasis on versatile functionalities. Following a brief introduction of basic concepts and the potential virtues of MMPFs, we give a snapshot of the historical perspective of MMPFs since 1991. We then summarize four effective strategies implemented frequently to construct prototypal MMPFs. MMPFs represent a resurging class of promising functional materials, highlighted with diverse applications including guest-molecule adsorption and separation, catalysis, nano-thin films and light-harvesting.
We report on the formation of Langmuir films of 5,10,15,20-tetra(4-pyridyl) 21H,23H-porphine, hereafter named tetrapyridyl porphyrins with distinct central ions (2H+, Zn2+, Cu2+, Ni2+). The films were characterized with surface pressure and surface potential isotherms and in situ UV–vis absorbance. The measurements indicated strong aggregation of porphyrin monomers at the air–water interface, with a red shift of the Soret band in comparison with the spectrum obtained from CHCl3 solutions. The shift was larger for the non-substituted H2TPyP, and depended on the metal ion. Significantly, aggregation occurred right after spreading of the Langmuir film, with no further shifts in the UV–vis spectra upon compression of the film, or even after transferring them onto solid substrates in the form of Langmuir–Blodgett (LB) films. The buildup of LB films from H2TPyP and ZnTPyP was monitored with UV–vis spectroscopy, indicating an equal amount of material deposited in each deposition step. Using FTIR in the transmission and reflection modes, we inferred that the H2TPyP molecules exhibit no preferential orientation in the LB films, while for ZnTPyP there is preferential orientation, with the porphyrin molecules anchored to the substrate by the lateral pyridyl groups.
The microwave synthesis of a series of platinum(II) phosphine complexes is reported. The complexes dppePtCl2 (dppe = bis(diphenylphosphino)ethane), dpppPtCl2 (dppp = bis(diphenylphosphino)propane), dppmPtCl2 (dppm = bis(diphenylphosphino)methane) and cis-(Ph3P)2PtCl2 are synthesized from the reaction of potassium tetrachloroplatinate(II) and the phosphine. The isolated yields are 65% or better.
Dynamic optical nonlinearities in free base tetrapyridylporphyrin (H 2 TPyP) solutions were investigated at 532 nm with the Z-scan technique. We observed a reverse saturable absorption process that was found to have a fast contribution related to the singlet population and a slow accumulative contribution arising from the triplet population. The optical excitations and subsequent relaxations can be interpreted with a five-energy-level diagram that allows determination of the excited states photophysical parameters such as triplet and singlet absorption cross-sections and the intersystem crossing time. Copyright © 2003 Society of Porphyrins & Phthalocyanines.
The photoconductivity of nanorods self-assembled from meso-tetrakis(4-sulfonatophenyl)porphine is described. The nanorods are insulating in the dark. Upon illumination with 488 nm light, the nanorods become photoconductive, exhibiting a rapid turn on/off (<100 ms) of the current when the light is turned on/off. This photoconductivity grows over hundreds of seconds with light exposure and decays slowly when the light is off. The nanorods can be trained via an applied bias to exhibit a short-circuit photocurrent (with corresponding open-circuit photovoltage) that flows in the direction opposite that of the training bias. A qualitative model is proposed, in which conduction occurs through the tightly coupled LUMOs of close-packed porphyrin molecules.
For the test system zinc tetraphenylporphyrin in ethanol, the S2−S0 and S1−S0 absorption and emission spectra and fluorescence quantum yields have been measured as a function of excitation wavelength within the Soret and Q-bands under conditions where self-absorption of emission and solute aggregation are either eliminated or properly compensated. Under these conditions, the smallest S2−S0 Stokes shift yet measured, 115 cm-1, and the largest S2−S0 absolute fluorescence quantum yield yet measured, 1.84 × 10-3, are obtained. Accurate measurements of the relative quantum yields of S2−S0 to S1−S0 emission as a function of excitation wavelength reveal that a fast radiationless process that bypasses S1 is operative among states accessed at excitation energies that span the Soret band. The data can be interpreted using the evidence of Yu, Baskin, and Zewail that a second excited state, S2‘, contributes a small fraction of the Soret band's integrated molar absorptivity and is responsible for an increasing fraction of photon absorption on both the red edge of the Soret band at λex > 430 nm and the blue at λex < 409 nm. The lifetimes of the S2 and S1 states have also been measured under similar conditions; the values obtained confirm previous measurements.
A treatment of the exciton coupling interaction including the solvent stabilization effect is given. The method is successfully applied to porphyrin dimer and trimer: the maxima of the Soret bands can be predicted with a high accuracy. The effect of exciton coupling on the photophysical properties of basket handle cofacial, doubly linked porphyrin dimer and trimer is investigated and compared to that in the singly linked dimer. Exciton coupling is very weak for the latter, whose chromophores behave independently from each other: the quantum yields of the singlet decay pathways (fluorescence, intersystem crossing, internal conversion) remain approximately the same as in the monomer. For the face-to-face compounds, the drastic decrease of the fluorescence and triplet yield could not be entirely explained in terms of the unique exciton coupling effect. The existence of a low virtual charge-transfer state lying near above the lowest singlet excited state is postulated and discussed. It allows us (i) to explain the increase of the internal conversion rate constant at the expense of the other radiative and radiationless processes and (ii) to account for the invariance of the singlet and triplet lifetimes of excited dimer and trimer with respect to the monomer.
Absorption and emission spectra and emission quantum yields are given for free-base (H/sub 2/), Zn, Cu, and Pd derivatives of tetrakis(perfluorophenyl)porphyrin (TFPP). The four-orbital model is used to rationalize differences in the optical properties among the derivatives of TFPP and the same derivatives of porphine (P), octaethylporphyrin (OEP), and tetraphenylporphyrin (TPP). It is concluded from absorption data that the energy difference between the two excited singlets, i.e., /sup 1/E(a/sub 2u/,e/sug g/) - /sup 1/E(a/sub 1u/,e/sub g/), decreases along the series Pd > Cu > Zn > H/sub 2/ and also along the series OEP > P > TFPP > TPP. The theory and date are reviewed, and it is concluded that the energy difference between the two excited triplets, i.e., /sup 3/E(a/sub 2u/,e/sub g/) - /sup 3/E(a/sub 1u/,e/sub g/), also decreases along these series. However the condition of degeneracy, e.g., /sup 1/E(a/sub 2u/,e/sub g/) - /sup 1/E(a/sub 1u/,e/sub g/) = 0, occurs for different molecules in the singlet and triplet cases. Theory also suggests that if /sup 3/E(a/sub 2u/,e/sub g/) > /sup 3/E(a/sub 1u/,e/sub g), the molecule should form a /sup 2/A/sub 1u/ cation radical and if /sup 3/E(a/sub 2u/,e/sub g/) < /sup 3/E(a/sub 1u/,e/sub g/) the molecule should form a /sup 2/A/sub 2u/ radical. 4 figures, 2 tables.
The binding constant of a novel ruthenium–porphyrin to calf thymus DNA is reported. In addition, the ruthenium–porphyrin photocleaves circular plasmid DNA in buffered solutions when irradiated with a 50W tungsten-halogen lamp. The ruthenium–porphyrin shows the ability to diffuse into normal and skin cancer cells and over a 6day period in the absence of light shows no toxicity, however, complete cell death is observed when these cells are irradiated for 1h with a 60W tungsten lamp.
The aim of this study is to verify if water-soluble porphyrins can be used as proteasome inhibitors. We have found that cationic porphyrins inhibit proteasome peptidase activities much more effectively than the corresponding anionic derivatives. The relevance of electrostatics in driving porphyin-proteasome interactions has been confirmed by the observation that the inhibitory efficiency of the cationic macrocycles decreases with the number of positive substituents. We have also investigated various metalloporphyrins, which differ due to the different propension of the central metal ion toward axial coordination. Our experimental results indicate that the naked cationic porphyrins are the most active in reversibly inhibiting the three main protease activities of the proteasome in the micromolar range. A spectroscopic characterization of porphyrin-proteasome interactions by UV-vis spectra parallels the results of inhibition assays: the higher the inhibitory effect the stronger the spectroscopic variations are. To interpret the action of porphyrins at a molecular level, we have performed calculations evidencing that cationic porphyrins may hinder the access to the canonical proteolytic site on the proteasome β5 subunit. In particular, an inspection of the top-scoring docking modes shows that the tetracationic porphyrin blocks the catalytic pocket, close to the N termini of the β5 proteasome subunit, more efficiently than its anionic counterpart. Proteasome inhibition activity of porphyrins unites their known anticancer properties making them suitable as a scaffold for the design of novel multitargeted molecules.
Photodynamic therapy (PDT) is a promising new treatment for cancer that has been recently accepted in the clinic. PDT involves the localization of a light-sensitive drug (photosensitizer) in the target tissue prior to illumination using an appropriate wavelength. Cytotoxic agents generated upon illumination trigger a cascade of biochemical responses that inactivate cancer cells either directly or through the induction of vascular stasis. These treatments are better tolerated as they destroy diseased tissue while leaving normal tissue intact. The haematoporphyrin derivative, Photofrin®, has been approved in a number of European and Asian countries, as well as in North America. To enhance the potential of PDT and explore its application for other conditions, second-generation photosensitizers are being rigorously investigated.
The conjugation of porphyrins to metal fragments is a strategy for making new compounds that are expected to combine the phototoxicity and the tumour-localization properties of the porphyrin chromophore with the cytotoxicity of the metal fragment for additive antitumour effect. We report here the preparation of new classes of porphyrin-ruthenium conjugates with potential bio-medical applications. Ruthenium was chosen because several Ru compounds have shown promising anticancer activity. The conjugation with the porphyrin moiety was accomplished either through peripheral pyridyl rings (e.g.meso-4′-tetrapyridylporphyrin, 4′TPyP) or through bpy units (e.g.meso-(p-bpy-phenyl)porphyrins, bpyn-PPs, n = 1-4). The number of Ru fragments attached to the porphyrins ranges from 1 to 4 and the total charge of the conjugates from -4 to +8. Different types of peripheral fragments, both Ru(iii) and Ru(ii), have been used: in some cases they are structurally similar to established anticancer compounds. Examples are [Na]4[4′ TPyP{trans-RuCl4(dmso-S)}4] (2), that bears four NAMI-type Ru(iii) fragments, or [4′TPyP{Ru([9]aneS3)(en)}4][CF 3SO3]8 (3) and [bpy4-PP{Ru([9]aneS3) (dmso-S)}4][CF3SO3]8 (9) (en = ethane-1,2-diamine, [9]aneS3 = 1,4,7-trithiacyclononane) that have four half-sandwich Ru(ii) compounds. The Ru fragments may either contain one or more labile ligands, such as in 2 or in 9, or be coordinatively saturated and substitutionally inert, such as in 3 or in [bpy4-PP{Ru([12]aneS4)} 4][CF3SO3]8 (11) ([12]aneS4 = 1,4,7,10-tetrathiacyclododecane). Most of the ruthenium-porphyrin conjugates described in this work are soluble - at least moderately - in aqueous solution and are thus suitable for biological investigations, in particular for cytotoxicity and photo-cytotoxicity tests.