Disubstituted Porphyrins Research Articles

Cellular Uptake and Phototoxicity Optimization of Arene Ruthenium Porphyrin Derivatives

In this study, dinuclear and tetranuclear arene ruthenium porphyrins were synthesized and assessed for their potential as photosensitizers (PSs) in photodynamic therapy (PDT) using the Colo205 colon cancer cell line as a model system. Reactive oxygen species (ROS) production, cellular uptake, impact on cell viability, and mechanisms of cell death induced by the synthesized compounds were comprehensively investigated. Our results revealed that the number of arene ruthenium units, as well as zinc (Zn) metalation of the porphyrin core, significantly influenced ROS production and increased it two-folds compared to the Zn-free analogs. The uptake of tetra-substituted Zn-porphyrins by the cancer cells increased to 2.8 nmol/106 cells compared to 0.6 nmol/106 cells of the disubstituted Zn-free and Zn-chelating porphyrins. The anticancer photo-activity of the complexes, where the percentage of metabolic activity of disubstituted Zn-porphyrins decreased to 26% when Zn was inserted, was compared to disubstituted Zn-free analogs. A further decrease in metabolic activity was observed, when the number of arene ruthenium units increased in the tetra-substituted Zn-porphyrins and tetra-substituted Zn-free compounds, reaching 4% and 14% respectively. Moreover, the percentage of apoptotic cell deaths increased to 40% when Zn was inserted into disubstituted porphyrins, compared to disubstituted Zn-free analog, and 50% when the number of arene ruthenium units increased. Overall, the tetra-substituted Zn chelating porphyrins exhibited the highest PDT efficiency, followed by the di-substituted Zn-porphyrins. These findings underscore the importance of structural design in optimizing the efficacy of arene ruthenium porphyrins as PSs for PDT, offering valuable insights for the development of targeted cancer therapeutics.

Chalcogen atom effect on the intersystem crossing kinetic constant of oxygen- and sulfur disubstituted heteroporphyrins.

The modulation of the photophysical properties of di-substituted porphyrin rings upon the oxygen and sulfur-for-nitrogen replacement has been investigated at density functional theory (DFT) and its time-dependent formulation (TDDFT). The considered properties range from structural behaviors and excitation energies to spin-orbit coupling (SOC) and nonradiative intersystem kinetic constants. Results show that the SOC strongly increase upon chalcogen substitution and, accordingly, the computed nonradiative kinetic constant also indicate an efficient singlet-triplet intersystem crossing in the sulfur containing macrocycle. The presented results indicate an alternative way to properly modulate the porphyrin's crucial properties for their use in photodynamic therapy, without resorting to the use of heavy atoms.

Synthesis of dipyroromethanes in water and investigation of electronic and steric effects in efficiency of olefin epoxidation by sodium periodate catalyzed by manganese tetraaryl andtransdisubstituted porphyrin complexes

Condensation of pyrrole with various aldehydes in the presence of BF3•etherate as an acid catalyst in water provides good yield of some dipyrromethanes. Prolongation of the reaction time with aldehydes substituted by electron-donating (mesityl) or electron-withdrawing (2,6-dichlorophenyl) groups on the ortho positions of the phenyl did not lead to decomposition or scrambling. Manganese trans disubstituted porphyrin complexes which derive from various dipyrromethanes and manganese tetraaryl porphyrin complexes including various substituents with different steric and electronic properties show good catalytic activity in epoxidation of alkenes by NaIO4in the presence of imidazole (ImH). The study of steric and electronic effects of the catalysts on the epoxidation of olefins shows that Mn-porphyrin complexes with more bulky and electron-releasing groups on meso phenyls could increase the epoxidation yield of most alkenes.

Rational Synthesis of 2-Bromoporphyrins and 2,12-Dibromoporphyrins

Bromoporphyrins were prepared by the metal-mediated self-condensation of brominated 1-formyldipyrromethanes. Depending on the conditions, Mg(II)-2,12-dibromoporphyrin and Mg(II)-2-bromoporphyrin could be obtained in up to 11% and 17% isolated yield, respectively. Zn(II) was also a viable templating metal. The positions of the bromine substituents were confirmed by 2D-NMR spectroscopic analysis and the X-ray crystal structure of a derivative. Suzuki and Sonogashira reactions of the bromoporphyrins yielded 2-substituted or 2,12-disubstituted porphyrins with red-shifted absorption and emission spectra. This method provides access to the minimalist core of β-mono- and β,β'-disubstituted porphyrins from readily available starting materials.

Aminophenyl/carboxyphenylporphyrins as sensitizers for dye-sensitized solar cells

A series of tetraphenyl meso-substituted porphyrins with either p-amino or p-carboxy substituents has been studied as dyes for standard dye-sensitized solar cells (DSSCs). The porphyrins with greater numbers of amino groups generally show greater efficiency, primarily due to higher photocurrents; open-circuit voltage and fill factors are comparable. The most efficient sensitizer was the trans disubstituted zinc porphyrin, with an overall solar energy conversion efficiency of 5.66%, slightly higher than the triamino zinc porphyrin at 5.18%. The improved efficiency is attributed to the well known push–pull effect in porphyrinsensitized DSSCs with electrondonating groups opposite to the electronwithdrawing anchoring (carboxy) groups. It is suggested that porphyrin derivatives with cis diaminophenyl groups show somewhat diminished efficiency due to difficulties with regeneration of the dye from its oxidized form.

Glucosylated steroid-porphyrins as new tools for nanotechnology applications

Two glucosylated steroid-modified porphyrins, differing in the number and type of ring substitutions, were taken into consideration as versatile chiral elements with possible applications in different environments. Three distinctive features of the title compounds were investigated by optical spectroscopy methods: (i) the formation of chiral mesoscopic structures in solution; (ii) the formation of Langmuir–Blodgett films on hydrophilic substrates; (iii) the inclusion and localization in a liposome formulation. Specifically, the aggregation propensity of mono- and disubstituted porphyrin scaffolds was studied in DMSO–H2O (40/60, v/v), where J-type aggregates were detected by the broadening and bathochromic shift of the Soret absorption band. Circular Dichroism (CD) experiments highlighted the occurrence of specific stereochemical interactions during the formation of such structures. The aggregation properties of the investigated compounds were further exploited in the formation of porphyrin multilayers through Langmuir–Blodgett deposition on hydrophilic quartz supports. The properties of the porphyrin films were characterized by pressure–area compression isotherms and optical (UV-Vis, CD, fluorescence) spectroscopy. Moreover, the interaction between the synthesized porphyrins and a membrane model represented by unilamellar 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) liposomes was investigated. In particular, the partition between the aqueous and lipid phases, and the location of the porphyrin derivatives in the lipid bilayer were studied by fluorescence methods. The reported results demonstrate the multitask versatility of the synthesized glucosylated steroid-porphyrins, exemplified by the formation of ordered structures in very different environments: chiral mesoscopic structures in solution, densely-packed films on inorganic supports, stable inclusion complexes in liposome formulations.

Theoretical studies of phenol disubstituted porphyrins

Calculations on neutral and oxidized phenol disubstituted porphyrins were performed. Two electron oxidation may be accompanied by loss of one or more protons at either the central NH positions or the outer OH positions. These latter oxidized and deprotonated structures may be stabilized by quinonelike forms. Our calculations support the idea that quinonelike structures are important, based both upon energetic and rotational barrier calculations.

Amphiphilic meso-Disubstituted Porphyrins: Synthesis and the Effect of the Hydrophilic Group on Absorption Spectra at the Air−Water Interface

Five amphiphilic meso-disubstituted porphyrins bearing one polar group were synthesized, and their monolayer films were prepared. Their limiting molecular areas obtained from pi-A isotherms were 0.5-0.6 nm2, which were smaller than those of the corresponding meso-tetrasubstituted porphyrins. At the air-water interface, the disubstituted porphyrins showed a broad band in visible absorption spectra compared with the solution state, and the red shift of the Soret band exhibited a significant dependence on the kind of hydrophilic groups at the meso positions. Interestingly, the monolayer of the disubstituted porphyrin bearing a carboxyphenyl group (1-CO2H) showed a blue shift of the Soret band by adding cadmium chloride to the subphase, and the spectra varied upon multilayer deposition. The observed phenomena were interpreted by using the exciton theory. The effect of hydrophilic substituents on the absorption spectra of disubstituted porphyrin monolayers is discussed.

Synthesis and physicochemical properties of some 5,15-diarylporphyrin derivatives

Several derivatives of meso-5,15-diarylporpyrins (1–4) and their metal complexes were prepared and their physicochemical properties were studied. Their magnetic properties were characterized by SQUID magnetometer. The temperature dependence of the molar magnetic susceptibility of the copper and vanadyl complex of 5,15-diphenylporphyrin (1-Cu, 1-VO) obeyed the Curie law and were almost identical with those of corresponding meso-tetraphenyl derivatives. In addition to the magnetic properties of disubstituted porphyrins, the properties of Langmuir film of meso-disubstituted porphyrins 2-H2 were investigated by π–A isotherms and visible absorption spectra.

Anion sensors based on β,β′-disubstituted porphyrin derivatives

The synthesis of a disulfonamide appended porphyrin receptor ( 1 ) for anionic guests is presented. The distinct attribute of the receptor, compared to other porphyrin based receptors, centers on the attachment of the anion binding site to the porphyrin chromophore's β-positions through a polycyclic conjugated linkage. UV–vis and 1H NMR spectroscopy has been utilized to detect the binding of a variety of anions such as the halides, dihydrogen phosphate, hydrogen sulfate, and acetate. From these spectroscopic investigations, the strength of anion binding has been determined.

Superoxide dismutase mimetics: synthesis and structure–activity relationship study of MnTBAP analogues

Carboxylic ester and amide-substituted analogues of [5,10,15,20-tetrakis(4-carboxyphenyl)-porphyrinato]manganese(III) chloride (MnTBAP) were synthesized and assayed as potential superoxide dismutase (SOD) mimetics. The tetraester analogues 4a and 4b were found to have comparable SOD activity to the known SOD mimetic MnTBAP, while amides 4c– 4e exhibited reduced SOD activity. In the substituted methyl benzoate/acid and disubstituted porphyrin series, analogues 12c, 12f, and 12m were found to have comparable to improved SOD activity relative to MnTBAP and analogues 12j, 13a, and 13d exhibited improved activity in both the SOD and thiobarbituric acid reactive species (TBARS) assays relative to MnTBAP.

Representation of Nonplanar Structures of Nickel(II) 5,15-Disubstituted Porphyrins in Terms of Displacements along the Lowest-Frequency Normal Coordinates of the Macrocycle

The influence of substituents with increasing steric demands on the structure of nickel(II) 5,15-disubstituted porphyrins has been investigated with X-ray crystallography, UV−visible absorption spectroscopy, resonance Raman spectroscopy, molecular energy optimization calculations, and INDO/s molecular orbital calculations. Nickel 5,15-diphenylporphyrin is predicted by molecular mechanics calculations to be a mixture of planar and nonplanar conformers. All of the nickel dialkylporphyrins (where the alkyl group is propyl, isopropyl, and tert-butyl) are calculated to be in a predominantly gabled (gab) conformation resulting from an αα orientation of the substituents with respect to the macrocycle. This nonplanar gab distortion is made up of a linear combination of distortions along the lowest-frequency out-of-plane macrocycle normal coordinates of A2u (doming) and B1u (ruffling) symmetry types. A higher energy stable αβ conformer is also predicted for dialkylporphyrins, and its nonplanar structure can be represented as an equal combination of distortions along the x- and y-components of the lowest-frequency Eg (waving) normal coordinate. The nonplanar structures calculated by using molecular mechanics have been structurally decomposed into the displacements along the lowest-frequency normal coordinate of each symmetry type, and the contributions of each type to the total distortion in the calculated structures agree well with contributions obtained from structural decompositions of the available X-ray crystal structures. The predicted gab distortion is confirmed most convincingly by the X-ray crystal structure of [5,15-di-tert-butylporphinato]nickel(II) which is found to be in a gab αα conformation. Finally, INDO/s calculations show that the red shifts in the absorption spectra of the nickel disubstituted porphyrins are caused by the increasing nonplanarity resulting from increasing steric crowding within the series.

Synthesis of β-substituted porphyrins using palladium catalysed reactions

The palladium(II)-catalysed carbon-carbon-coupling reaction (Heck reaction) between a variety of metalated β-monohalosubstituted porphyrins (2-bromotetraphenylporphyrin, 2-bromo-3,7,8,12,13,17,18-heptaethylporphyrin, and 3(8)monoiodo-deuteroporphypin IX dimethyl ester) and a series of terminally substituted acetylenic derivatives, is reported. A few disubstituted porphyrin analogs were also synthesized using the corresponding β-dihalogenated porphyrin precursors.

Preparation of Porphyrins Having Phenylboronic Acid Groups

Abstract Tetra- and disubstituted porphyrins with p-dihydroxyborylphenyl groups on their meso-positions have been prepared as BNCT target compounds. The resulting porphyrins were solubilized upon formation of sugar-boronic acid complexes.

Purification and characterization of chicken erythrocyte ferrochelatase.

Ferrochelatase (EC 4.99.1.1) was purified 2000-fold to apparent homogeneity from isolated chicken erythrocyte mitochondria. The purified enzyme yields a single band on sodium dodecyl sulphate/polyacrylamide-gel electrophoresis with an apparent Mr of 42 000. The enzyme utilizes proto-, meso- and deutero-porphyrin with Km values of 37, 51 and 80 microM respectively. The disubstituted porphyrins 2,4-bisglycol deutero-porphyrin and 2,4-disulphonic deuteroporphyrin were not substrates. Mn2+, Hg2+, Pb2+ and Co2+ were strong inhibitors of the purified enzyme. Palmitic acid and oleic acid stimulated activity, whereas linoleic acid inhibited and phospholipids had variable effects. Chicken ferrochelatase was inhibited by N-ethylmaleimide and iodoacetamide. Inhibition by iodoacetamide was pseudo-first-order, but inhibition by N-ethylmaleimide appeared to be biphasic in nature with an initial high rate followed by a much lower rate of inactivation. The characteristics of the chicken erythrocyte enzyme are compared with those previously reported for mammalian liver ferrochelatase.

Spectral properties of protonated Schiff base porphyrins and chlorins. INDO-CI calculations and resonance Raman studies

INDO-CI calculations successfully reproduce the striking changes in optical spectra that occur upon protonation of mono- and disubstituted porphyrin, chlorin, and bacteriochlorin Schiff base complexes. They ascribe the changes to Schiff base C=N ..pi..* orbitals which drop in energy upon protonation and mix with and perturb the ..pi..* orbitals of the macrocycle, a result consistent with resonance Raman data. The perturbation is predicted to affect not only transition energies and intensities but also dipole moment directions. The symmetry of the porphyrin and the substitution site of the chlorin are shown to play an important role, especially in governing whether the lowest energy transition will red shift or blue shift. Blue shifts are calculated for protonation of ketimine and enamine isomers of pyrochlorophyll a (PChl). Comparison with reported optical spectra suggests that PChl a Schiff base may undergo isomerization upon protonation. Resonance Raman data on CHO, CHNR, CHNHR/sup +/, and pyrrolidine adducts of chlorin demonstrate the isolation of the peripheral C=O and C=N groups from the macrocycle ..pi.. system intramolecular hydrogen bonding, and selective enhancement of v/sub C=N/ for those species with a split Soret band. V/sub C=N/ is observed with 488.0-nm excitation into the lower-energy Soret and absent for 406.7-nmmore » excitation into the higher-energy Soret, a result predicted by the calculations. 44 references, 10 figures, 2 tables.« less

Bovine ferrochelatase. Kinetic analysis of inhibition by N-methylprotoporphyrin, manganese, and heme.

The terminal enzyme of the heme biosynthetic pathway, ferrochelatase (protoheme ferrolyase EC 4.99.1.1), has been purified to apparent homogeneity from bovine liver mitochondria using a scheme similar to that reported by Taketani and Tokunaga (Taketani, S. and Tokunaga, R. (1981) J. Biol. Chem. 256, 12748-12753) for purification of the enzyme from rat liver. The final yield was 49% with a 2000-fold purification. Ferrochelatase has an apparent molecular weight of approximately 40,000 by both sodium dodecyl sulfate-polyacrylamide gel electrophoresis and column chromatography on Sepharose CL-6B in the presence of 0.5% sodium cholate. The purified enzyme was only slightly stimulated by added lipid and was inhibited by Mn2+, Pb2+, and Hg2+. Bovine ferrochelatase utilized proto-, meso-, and deuteroporphyrin, but not disubstituted porphyrins (2,4-disulfonic and 2,4-bisglycol deuteroporphyrin). N-Methylprotoporphyrin, a toxic by-product of the metabolism of some drugs, was found to inhibit ferrochelatase in a competitive fashion with respect to porphyrin with a Ki of 7 nM and uncompetitive with respect to iron. Manganese inhibits ferrochelatase competitively with respect to iron (Ki = 15 microM) and noncompetitively with respect to the porphyrin substrate. Heme, one of the products, is a noncompetitive inhibitor with respect to iron. These findings lead to a sequential Bi Bi kinetic model for ferrochelatase with iron binding occurring prior to porphyrin binding and heme being released prior to the release of two protons.

The mixed‐aldehyde synthesis of difunctional tetraarylporphyrins

AbstractThe synthesis is reported of nine unsymmetrical, meso‐substituted porphyrins. Among the compounds prepared are the following 5‐(R)‐10,15,20‐tri‐p‐tolylporphyrins; R = 2,6‐dinitrophenyl, 4‐hydroxy‐3‐ethoxy‐phenyl, 4‐hydroxy‐3‐methoxy‐5‐nitrophenyl, 5‐hydroxy‐2‐nitrophenyl and 4‐hydroxy‐3‐nitrophenyl. Other porphyrins reported include 5‐(2‐(1‐butoxy)phenyl)‐15‐(2‐nitrophenyl)‐10‐15‐di‐p‐tolylporphyrin and the two 5‐(R)‐10‐15,20‐tripropylporphyrins in which R = 2‐nitrophenyl and 2‐hydroxyphenyl. The disubstituted porphyrins offer a rational route to the synthesis of difunctional “tailed‐porphyrins”.