Porphyrin-based Compounds Research Articles

Drug delivery strategies for porphyrin-based photosensitizers in photodynamic antimicrobial chemotherapy

In the face of increasing antimicrobial resistance (AMR) and the looming threat of a return to a pre-antibiotics era, the exploration of alternative antimicrobial strategies becomes imperative. Among these, Photodynamic Antimicrobial Chemotherapy (PACT) stands out as a promising solution due to its multi-target principle, diverging from the key-lock mechanism inherent in conventional antibiotics. However, the hydrophobic nature, non-targeted distribution, stability issues, and limited tissue penetration of photosensitizers (PSs), particularly the extensively studied porphyrin-based compounds, pose structural limitations impacting their bioavailability and effective delivery to target sites. Therefore, various delivery strategies are adopted to improve their effectiveness in PACT. This includes attaching the PS to a variety of delivery vehicles such as nanoparticles, and liposomes, or encapsulating them in nanostructures, such as micelles or dendrimers. This helps protect the PS from degradation, improve their solubility and bioavailability, and enhance their photophysical and photochemical properties, ultimately improving their effectiveness in PACT. In this paper, recent studies focusing on strategies used to improve the delivery of porphyrin-based PS in PACT are reviewed.

In Vivo and In Vitro Antioxidant Activity of Less Polar Fractions of Dasycladus vermicularis (Scopoli) Krasser 1898 and the Chemical Composition of Fractions and Macroalga Volatilome.

The present research is a comprehensive investigation of Dasycladus vermicularis (Scopoli) Krasser 1898 from the Adriatic Sea (Croatia) regarding volatilome–volatile organic compounds (VOCs, mostly nonpolar compounds) and less polar nonvolatile compounds for the first time. Headspace solid-phase microextraction (HS-SPME) and hydrodistillation (HD) were used showing the great volatilome variability among fresh (HS-FrDV and HD-FrDV) and dried (HS-DrDV and HD-DrDV) samples after GC–MS analysis. Aromatic aldehydes were dominant in both fresh and air-dried HS samples with benzaldehyde as the most abundant in fresh samples and decreasing 2.7–3.7 times after drying together with 2-phenylbut-2-enal that was not present after drying. Aliphatic compounds (unsaturated hydrocarbons in HS-FrDV; saturated hydrocarbons in HS-DrDV) were also present. C11-hydrocarbons (dictyopterpene C’ and dictyopterpene D’) were detected in HS-FrDV. (E)-Phytol was the most dominant compound in HD-FrDV and HD-DrDV. Diterpene alcohols (cembra-4,7,11,15-tetraen-3-ol and (Z)-falcarinol) and sesquiterpene alcohol, cubenol, were dominant in HD-FrDV, and their abundance decreased after drying. C13-norisoprenoides (α-ionone and β-ionone) increased after drying. Aliphatic compounds were present in both HD-FrDV and HD-DrDV samples. The less polar nonvolatile compounds in the obtained fractions F3 and F4 were analysed and identified by UHPLC-ESI(+)-HRMS. Identified compounds belonged to a group of pigments (7 compounds), fatty acid derivatives (13 compounds), as well as steroids and terpenes (10 compounds). Porphyrin-based compounds (C55H74N4O5–7), xanthophylls, sphingolipid compounds, fatty acid amides, and phytosterols represented the majority of identified compounds. By implementing both in vitro and in vivo assays for antioxidant activity determination, F3 showed a higher activity than F4. Inhibitory concentrations (IC50) for F3 and F4 were 498.00 ± 0.01 µg/mL and 798.00 ± 0.81 µg/mL, respectively, while a 1.5-fold reduction in the ROS level was observed after pre-treatment of zebrafish larvae with 45 µg/mL of F3.

A Brief Introduction to Porphyrin Compounds used in Tumor Imaging and Therapies.

As a group of heterocyclic macrocycle organic natural compounds occurring universally in animal tissues and plants, porphyrins are composed of four modified pyrrole subunits. Porphyrin analogues/ derivatives possess multiple biochemical properties because of their unique structures and have been extensively investigated in cancer treatment. Studies have shown that porphyrins and their derivatives have the ability to locate tumor cells in a variety of human cancers, and these compounds not only exhibit potent therapeutic effects as photodynamic agents but also show promising properties in medicinal imaging, such as MRI, photoacoustic imaging, fluorescence imaging, and PET/SPECT imaging. This paper reviews the recent reports of porphyrin derivatives as therapeutic agents used in tumor therapies, such as sonodynamic therapy, photodynamic therapy and radiotherapy, as well as the imaging agents for multimodality tumor imaging. The limitations of porphyrin-based compounds in tumor treatments and future prospects are also summarized.

Towards self-doping multimetal porphyrin systems

An approach for the possible production of novel bimetallic self-doped porphyrin-based compounds of potential interest in material science is reported. Heating Cu(II)tetraphenylporphyrin (TPPCu) with chromocene at 120°C in benzonitrile affords the crystalline multimetal porphyrin system TPPCu/TPPCr in good yield. The X-ray single crystal structural analysis reveals a random distribution of TPPCu and TPPCr, with a Cu:Cr ratio of 71(2):29(2)%. Exploratory DFT calculations of TPPCu/TPPCr indicate little if any electron transfer. In contrast, calculations of a hypothetical cationic TPPCu/TPPRu system indicates the possibility of self-doping.

Antibacterial Activity of Synthetic Cationic Iron Porphyrins.

Widespread antibiotic resistance demands new strategies for fighting infections. Porphyrin-based compounds were long ago introduced as photosensitizers for photodynamic therapy, but light-independent antimicrobial activity of such compounds has not been systematically explored. The results of this study demonstrate that synthetic cationic amphiphilic iron N-alkylpyridylporphyrins exert strong bactericidal action at concentrations as low as 5 μM. Iron porphyrin, FeTnHex-2-PyP, which is well tolerated by laboratory animals, efficiently killed Gram-negative and Gram-positive microorganisms. Its bactericidal activity was oxygen-independent and was controlled by the lipophilicity and accumulation of the compound in bacterial cells. Such behavior is in contrast with the anionic gallium protoporphyrin IX, whose efficacy depends on cellular heme uptake systems. Under aerobic conditions, however, the activity of FeTnHex-2-PyP was limited by its destruction due to redox-cycling. Neither iron released from the Fe-porphyrin nor other decomposition products were the cause of the bactericidal activity. FeTnHex-2-PyP was as efficient against antibiotic-sensitive E. coli and S. aureus as against their antibiotic-resistant counterparts. Our data demonstrate that development of amphiphilic, positively charged metalloporphyrins might be a promising approach in the introduction of new weapons against antibiotic-resistant strains.

Synthesis of Dithiophene-Monobenzo-Tetra(4-isopropylphenyl)Porphyrin

Porphyrins have been recognized as promising leads for harvesting applications due to their strong absorption and ability for extended π-conjugation. There have been several porphyrin-based compounds that have been developed in the hopes of increasing the efficiency of these applications. For instance, thiophene derivatives have been studied with porphyrins due to their use as a π-linker, facile functionalization with both electron withdrawing and electron donating groups, and capability to redshift absorption spectra of the porphyrin. In this report, the synthesis, MALDI, and crystal structure of a new β-extended disubstituted-vinylthiophene-monobenzo-tetra(4-isopropylphenyl)porphyrin is discussed. Figure 1

Porphyrins to restrict progression of pancreatic cancer by stabilizing KRAS G-quadruplex: In silico, in vitro and in vivo validation of anticancer strategy

KRAS, a frequently mutated G-quadruplex forming proto-oncogene is responsible for almost every type of cancer which can form a parallel G-quadruplex structure in the promoter region. G-quadruplex structure is one of the most important drug targets for modern cancer therapy for their unique structure and specificity. Here, we have screened several synthetic porphyrin-based compounds as potential KRAS G-quadruplex stabilizing ligands, using molecular modeling and docking studies. Two novel porphyrins: Porphyrin-1(Cobalt containing) and Porphyrin-2 (Palladium containing) evidenced high affinity towards KRAS-promoter/G-quadruplex. As KRAS mutation is prevalent in pancreatic cancer, the efficacy of these ligands against human pancreatic ductal carcinoma cell line PANC-1 and MiaPaCa2 were examined. Both the Porphyrins exhibited significant cytotoxicity and block metastasis by inhibiting Epithelial to messenchymal transition. In vivo studies confirmed both porphyrin compounds to be effective against EAC tumors along with significantly low toxicity against normal Swiss albino mice. The expression of KRAS gene in porphyrin-treated PANC-1, MiaPaCa2 and tumor-derived EAC cells were drastically reduced at both protein and RNA levels. Thus interaction of porphyrin-based ligands with G-quadruplex DNA at the promoter region of KRAS, might be utilized as a target for anticancer therapeutic strategy.

The role of carboxymethyl substituents in the interaction of tetracationic porphyrins with DNA

Cationic porphyrin-based compounds capable of interacting with DNA are currently under extensive investigation as prospective anticancer and anti-infective drugs. One of the approaches to enhancing the DNA-binding affinity of these ligands is chemical modification of functional groups of the porphyrin macrocycle. We analyzed the interaction with DNA of novel derivatives containing carboxymethyl and ethoxycarbonylmethyl substituents at quaternary nitrogen atoms of pyridinium groups at the periphery of the porphyrin macrocycle. The parameters of binding of 5,10,15,20-tetrakis(N-carboxymethyl-4-pyridinium)porphyrin (P1) and 5,10,15,20-tetrakis(N-ethoxycarbonylmethyl-4-pyridinium)porphyrin (P2) to double-stranded DNA sequences of different nucleotide content were determined using optical spectroscopy. The association constant of P1 interaction with calf thymus DNA (K=3.4×10(6)M(-1)) was greater than that of P2 (K=2.8×10(5)M(-1)). Preferential binding of P1 to GC- rather than AT-rich oligonucleotides was detected. In contrast, P2 showed no preference for particular nucleotide content. Modes of binding of P1 and P2 to GC and AT duplexes were verified using the induced circular dichroism spectra. Molecular modeling confirmed an intercalative mode of interaction of P1 and P2 with CpG islands. The carboxyl groups of the peripheral substituent in P1 determine the specific interactions with GC-rich DNA regions, whereas ethoxycarbonylmethyl substituents disfavor binding to DNA. This study contributes to the understanding of the impact of peripheral substituents on the DNA-binding affinity of cationic porphyrins, which is important for the design of DNA-targeting drugs.

Validation of Quantitative Structure-Activity Relationship (QSAR) Model for Photosensitizer Activity Prediction

Photodynamic therapy is a relatively new treatment method for cancer which utilizes a combination of oxygen, a photosensitizer and light to generate reactive singlet oxygen that eradicates tumors via direct cell-killing, vasculature damage and engagement of the immune system. Most of photosensitizers that are in clinical and pre-clinical assessments, or those that are already approved for clinical use, are mainly based on cyclic tetrapyrroles. In an attempt to discover new effective photosensitizers, we report the use of the quantitative structure-activity relationship (QSAR) method to develop a model that could correlate the structural features of cyclic tetrapyrrole-based compounds with their photodynamic therapy (PDT) activity. In this study, a set of 36 porphyrin derivatives was used in the model development where 24 of these compounds were in the training set and the remaining 12 compounds were in the test set. The development of the QSAR model involved the use of the multiple linear regression analysis (MLRA) method. Based on the method, r2 value, r2 (CV) value and r2 prediction value of 0.87, 0.71 and 0.70 were obtained. The QSAR model was also employed to predict the experimental compounds in an external test set. This external test set comprises 20 porphyrin-based compounds with experimental IC50 values ranging from 0.39 μM to 7.04 μM. Thus the model showed good correlative and predictive ability, with a predictive correlation coefficient (r2 prediction for external test set) of 0.52. The developed QSAR model was used to discover some compounds as new lead photosensitizers from this external test set.

Abstract B56: Organelle targeted photodynamic therapy

Abstract The success of a cancer treatment is directly related to its ability to selectively kill cancer cells. Photodynamic therapy (PDT) with a photosensitizer (PS) that targets mitochondria causes a prompt release of cytochrome c into the cytoplasm and activation of caspases-9 and -3, among other caspases, that are responsible for initiating cell degradation. Photofrin is the FDA approved drug for PDT. Mitochondria have repeatedly been implicated as primary targets of porphyrin mediated PDT. However, a systematic study to direct the PDT drugs towards their cellular target, mitochondria of the cancer cell, is not yet fully explored. Phthalocyanins (Pc) are a class of compounds, which are known to successfully address the drawbacks exhibited by the porphyrin-based compounds. PDT, using the second-generation Pc, causes mitochondrial damage and induces apoptosis. However, the Pc molecules are hydrophobic and must be encapsulated within a liposomal formulation for successful delivery. Given that most effective PDT drug candidates act on the mitochondria of cancer cells and their hydrophobicity require suitable delivery vehicles for their intracellular accumulation, we hypothesize that the construction of engineered targeted drug delivery systems to direct PDT drugs to the mitochondria of the cancer cells would allow an effective phototherapeutic action. This would result in a higher local concentration of singlet oxygen in the mitochondria of cancer cells. In order to study this hypothesis, we have initiated the synthesis of a series of mitochondria targeting polymers to study nanoparticle (NP) assisted targeted delivery and anticancer properties of metallo phthalocyanins. The synthesis and biological activity of these constructs will be discussed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B56.

ChemInform Abstract: The Role of Porphyrin Chemistry in Tumor Imaging and Photodynamic Therapy

AbstractReview: 205 refs.

The role of porphyrin chemistry in tumor imaging and photodynamic therapy

In recent years several review articles and books have been published on the use of porphyrin-based compounds in photodynamic therapy (PDT). This critical review is focused on (i) the basic concept of PDT, (ii) advantages of long-wavelength absorbing photosensitizers (PS), (iii) a brief discussion on recent advances in developing PDT agents, and (iv) the various synthetic strategies designed at the Roswell Park Cancer Institute, Buffalo, for developing highly effective long-wavelength PDT agents and their utility in constructing the conjugates with tumor-imaging and therapeutic potential (Theranostics). The clinical status of certain selected PDT agents is also summarized (205 references).

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

Oxidative stress has become widely viewed as an underlying condition in a number of diseases, such as ischemia-reperfusion disorders, central nervous system disorders, cardiovascular conditions, cancer, and diabetes. Thus, natural and synthetic antioxidants have been actively sought. Superoxide dismutase is a first line of defense against oxidative stress under physiological and pathological conditions. Therefore, the development of therapeutics aimed at mimicking superoxide dismutase was a natural maneuver. Metalloporphyrins, as well as Mn cyclic polyamines, Mn salen derivatives and nitroxides were all originally developed as SOD mimics. The same thermodynamic and electrostatic properties that make them potent SOD mimics may allow them to reduce other reactive species such as peroxynitrite, peroxynitrite-derived CO(3)(*-), peroxyl radical, and less efficiently H(2)O(2). By doing so SOD mimics can decrease both primary and secondary oxidative events, the latter arising from the inhibition of cellular transcriptional activity. To better judge the therapeutic potential and the advantage of one over the other type of compound, comparative studies of different classes of drugs in the same cellular and/or animal models are needed. We here provide a comprehensive overview of the chemical properties and some in vivo effects observed with various classes of compounds with a special emphasis on porphyrin-based compounds.

Porphyrin and Nonporphyrin Photosensitizers in Oncology: Preclinical and Clinical Advances in Photodynamic Therapy

Photodynamic therapy (PDT) is now a well-recognized modality for the treatment of cancer. While PDT has developed progressively over the last century, great advances have been observed in the field in recent years. The concept of dual selectivity of PDT agents is now widely accepted due to the relative specificity and selectivity of PDT along with the absence of harmful side effects often encountered with chemotherapy or radiotherapy. Traditionally, porphyrin-based photosensitizers have dominated the PDT field but these first generation photosensitizers have several disadvantages, with poor light absorption and cutaneous photosensitivity being the predominant side effects. As a result, the requirement for new photosensitizers, including second generation porphyrins and porphyrin derivatives as well as third generation photosensitizers has arisen, with the aim of alleviating the problems encountered with first generation porphyrins and improving the efficacy of PDT. The investigation of nonporphyrin photosensitizers for the development of novel PDT agents has been considerably less extensive than porphyrin-based compounds; however, structural modification of nonporphyrin photosensitizers has allowed for manipulation of the photochemotherapeutic properties. The aim of this review is to provide an insight into PDT photosensitizers clinically approved for application in oncology, as well as those which show significant potential in ongoing preclinical studies.

Porphyrin-Carbohydrate Conjugates: Impact of Carbohydrate Moieties in Photodynamic Therapy (PDT)

In recent years, a number or review articles describing the utility of porphyrin-based compounds in photodynamic therapy have been published. Currently, efforts are also underway in various laboratories to increase the tumor-specificity by developing target-specific photosensitizers. One of such attempts has been to synthesize a series of carbohydrate-porphyrin conjugates and investigate their ability to target carbohydrate- recognized proteins, which are known for their high expression in certain tumors. The present article is focused on the synthesis and biological significance of carbohydrate conjugated photosensitizers.

A Novel Approach to a Bifunctional Photosensitizer for Tumor Imaging and Phototherapy

Optical imaging has attracted a great attention for studying molecular recognitions because minute fluorescent tracers can be detected in homogeneous and heterogeneous media with existing laboratory instruments. In our preliminary study, a clinically relevant photosensitizer (HPPH, a chlorophyll-a analog) was linked with a cyanine dye (with required photophysical characteristics but limited tumor selectivity), and the resulting conjugate was found to be an efficient tumor imaging (fluorescence imaging) and photosensitizing agent. Compared to HPPH, the presence of the cyanine dye moiety in the conjugate produced a significantly higher uptake in tumor than skin. At a therapeutic/imaging dose, the conjugate did not show any significant skin phototoxicity, a major drawback associated with most of the porphyrin-based photosensitizers. These results suggest that tumor-avid porphyrin-based compounds can be used as "vehicles" to deliver the desired fluorescent agent(s) to tumor. The development of tumor imaging or improved photodynamic therapy agent(s) by itself represents an important step, but a dual function agent (fluorescence imaging and photodynamic therapy) provides the potential for tumor detection and targeted photodynamic therapy, combining two modalities into a single cost-effective "see and treat" approach.

Photoinduced Electron Transfer in Double-Bridged Porphyrin−Fullerene Triads

Electron and energy transfer reactions of porphyrin-porphyrin-fullerene triads (P2P1C) with controllable sandwich-like structures have been studied using spectroscopic and electrochemical methods. The stabile, stacked structure of the molecules was achieved applying a two-linker strategy developed previously for porphyrin-fullerene dyads. Different triad structures with altered linker positions, linker lengths, and center atoms of the porphyrin rings were studied. The final charge-separated (CS) state and the different transient states of the reactions have been identified and energies of the states estimated based on the experimental results. In particular, a complete CS state P2(+) P1C- was achieved in a zinc porphyrin-free-base porphyrin-fullerene triad (ZnP2t9P1C) in both polar (benzonitrile) and nonpolar (toluene) solvents. The lifetime of this state was longer living in the nonpolar solvent. An outstanding feature of the ZnP2t9P1C triad is the extremely fast formation of the final CS state, P2(+) P1C-. This state is formed after primary excitation of either zinc porphyrin or free-base porphyrin chromophores in less than 200 fs. Although the intermediate steps between the locally excited states and the final CS state were not time-resolved for this compound, the process is clearly multistep and the fastest ever observed for porphyrin-based compounds.

Synergic Photosensitizers: A New Trend in Photodynamic Therapy

Photodynamic therapy (PDT) has become an increasingly important method for the chemotherapeutic treatment of some cancers. It involves the systemic, topical, or intraperitoneal administration of a nontoxic drug called a photosensitizer, which, to some extent, preferentially localizes in the tumor [1,2]. When the tumor is illuminated with the wavelength of light that is absorbed by the dye, in the presence of oxygen, toxic oxygen reactive species are producedand they can cause tissue necrosis or apoptosis by a combination of mechanisms [3]. The Phthalocyanine complexhas recently become very popular in different areas of science and technology. Due to many useful physical and chemical properties, these complexes have found use in opticaland semi conducting devices [4], electrochemistry [5], catalysis [6], analytical chemistry [7] and photodynamic therapy [8]; and have been extensively reviewed in the last decade [9,10]. The main disadvantage of using phthalocyanines is their enhanced tendency to participate in aggregation processes dependent on the central metal ion, which leads to low solubility in biological aqueous medium. Photosensitizers could be natural or synthetic [11]. In general,the three main families of photosensitizers are porphyrin-based compounds, chlorophyll-based compounds or phthalocyanine derivatives [12]. A number of novel compounds consisting of multifunctional ligands, such as phthalocyanine-nucleobase conjugates, phthalocyanine-dendrimers and crown ethers or macro-aza group moieties have been reported recently. The objective of this review is to describe recent progress in photosensitizer concepts along with an indication of some prominent synergic photosensitizers.

Porphyrin-based compounds exert antibacterial action against the sexually transmitted pathogens Neisseria gonorrhoeae and Haemophilus ducreyi

A series of porphyrin based compounds without (nMP) or with (MP) metals were found to have potent bactericidal action in vitro against the sexually transmitted pathogens Neisseria gonorrhoeae and Haemophilus ducreyi. nMP and MP did not show bactericidal activity against five species of lactobacilli. An MP containing gallium had the capacity to block a gonococcal infection in a murine vaginal model, indicating that its development as a topical microbicide to block sexually transmitted bacterial infections is warranted. In contrast to other bacterial species, loss of the gonococcal haemoglobin uptake system encoded by hpuB or energy supplied through the TonB-ExbB-ExbD system did not significantly affect levels of MP-susceptibility in gonococci. In contrast, mutations in gonococci that inactivate the mtrCDE-encoded efflux pump were found to enhance gonococcal susceptibility to nMPs and MPs while over-production of this efflux pump decreased levels of gonococcal susceptibility to these compounds.

Understanding the reaction that powers this world: Biomimetic studies of respiratory O2 reduction by cytochrome oxidase

Abstract Cytochrome c oxidase (CcO) is an enzyme that catalyzes efficient, selective, and fast reduction of molecular oxygen to water as a means of respiratory energy generation. The biomimetic approach provides a valuable alternative to traditional biochemical methods to unravel the structural and electronic properties of the CcO's catalytic (heme/CuB) site that endow the enzyme with its unique reactivity. However, the contribution of biomimetic studies of CcO to our understanding of CcO's biochemistry has been complicated by the lack of convincing evidence that the reactivity of the biomimetic analogs is relevant to that of CcO. Recently reported porphyrin-based compounds are the first analogs that reproduce key aspects of the reactivity of CcO toward O2. Extensive data collected with these biomimetic analogs demonstrate that the bimetallic nature of the CcO's catalytic site may be an adaptation to reduction of O2 under turnover-limiting electron flux; a monometallic heme-only site appears sufficient for rapid O2 reduction under physiologically relevant conditions of pH and electrochemical potential, provided that electron flow to the heme is not kinetically limited. These biomimetic data suggest that in CcO the distal Cu ion (CuB) may serve as an electron-preloading site to allow the enzyme to accumulate a sufficient number of external reducing equivalents before it even binds O2. This mechanism minimizes the population of enzymatic species containing partially reduced oxygen species.