A Comprehensive Study on Tetraaryltetrabenzoporphyrins.

Invited for the cover of this issue are the groups of Lungerich and Jux at the Friedrich-Alexander University Erlangen-Nuernberg. The image depicts the synthetic feasibility with a "TATBP tuning shop", which shows the change of the four meso aryl substituents to modify the performance of the molecule. Read the full text of the article at 10.1002/chem.201904718.

A Comprehensive Study on Tetraaryltetrabenzoporphyrins.

Tetraaryltetrabenzoporphyrins (TATBPs) show, due to their optoelectronic properties, rising potential as dyes in various fields of physical and biomedical sciences. However, unlike in the case of porphyrins, the potential structural diversity of TATBPs has been explored only to little extent, owed mainly to synthetic hurdles. Herein, we prepared a comprehensive library of 30 TATBPs and investigated their fundamental properties. We elucidated structural properties by X-ray crystallography and found explanations for physical properties such as solubility. Fundamental electronic aspects were studied by optical spectroscopy as well as by electrochemistry and brought in context to the stability of the molecules. Finally, we were able to develop a universal synthetic protocol, utilizing a readily established isoindole synthon, which gives TATBPs in high yields, regardless of the nature of the used arylaldehyde and without meticulous chromatographic purifications steps. This work serves as point of orientation for scientists, that aim to utilize these molecules in materials, nanotechnological, and biomedical applications.

Positive Charge on Porphyrin Ligand and Nature of Metal Center Define Basic Physicochemical Properties of Cationic Manganese and Iron Porphyrins in Aqueous Solution.

Recently, comprehensive studies on positively charged manganese porphyrins show that these compounds, known for their superoxide dismutase (SOD) mimetic ability, can be equally reactive toward a broad array of other redox active molecules of biological relevance present in a cellular milieu. In this context, the examination of some fundamental aspects of physicochemical behavior of metalloporphyrins behind their rich aqueous chemistry is believed to provide a valuable basis for the understanding of newly observed biological effects of these compounds in vivo and throw more light on a potential use of common SOD porphyrin mimetics for other redox active cellular targets in order to earn desirable therapeutic effects. Herein, we present versatile characteristics of highly positively charged Mn(P) and Fe(P) porphyrins (with up to +9 and +8 overall charge, respectively) with regard to their acid-base equilibria, metal coordination sphere, water-exchange dynamics, redox properties, and substitution behavior toward selected ligands. For the purpose of these comparative studies, we synthesized for the first time a 9-fold cationic manganese(III) porphyrin. The findings reported in this study enabled highlighting the most important similarities and differences characterizing the aqueous chemistry of positively charged manganese and iron porphyrins and, therefore, outlining the potential factors which can affect the intimate underlying mechanism behind the redox cycling of these metalloporphyrins.

Cellular Fates of Manganese(II) Pentaazamacrocyclic Superoxide Dismutase (SOD) Mimetics: Fluorescently Labeled MnSOD Mimetics, X-ray Absorption Spectroscopy, and X-ray Fluorescence Microscopy Studies.

Manganese(II) pentaazamacrocyclic complexes (MnPAMs) can act as small-molecule mimics of manganese superoxide dismutase (MnSOD) with potential therapeutic application in conditions linked to oxidative stress. Previously, the in vitro mechanism of action has been determined, their activity has been demonstrated in cells, and some representatives of this class of MnSOD mimetics have entered clinical trials. However, MnPAM uptake, distribution, and metabolism in cells are largely unknown. Therefore, we have used X-ray fluorescence microscopy (XFM) and X-ray absorption spectroscopy (XAS) to study the cellular fate of a number of MnPAMs. We have also synthesized and characterized fluorescently labeled (pyrene and rhodamine) manganese(II) pyane [manganese(II) trans-2,13-dimethyl-3,6,9,12,18-pentaazabicyclo[12.3.1]octadeca-1(18),14,16-triene] derivatives and investigated their utility for cellular imaging of MnPAMs. Their SOD activity was determined via a direct stopped-flow technique. XFM experiments show that treatment with amine-based manganese(II) pyane type pentaazamacrocycles leads to a 10-100-fold increase in the overall cellular manganese levels compared to the physiological levels of manganese in control cells. In treated cells in general, manganese was distributed throughout the cell body, with a couple of notable exceptions. The lipophilicity of the MnPAMs, examined by partitioning in octanol-buffer system, was a good predictor of the relative cellular manganese levels. Analysis of the XAS data of treated cells revealed that some fraction of amine-based MnPAMs taken up by the cells remained intact, with the rest transformed into SOD-active manganese(II) phosphate. Higher phosphate binding constants, determined from the effect of the phosphate concentration on in vitro SOD activity, were associated with more extensive metabolism of the amine-based MnPAMs to manganese(II) phosphate. In contrast, the imine-based manganese(II) pydiene complex that is prone to hydrolysis was entirely decomposed after uptake and free manganese(II) was oxidized to a manganese(III) oxide type species, in cytosolic compartments, possibly mitochondria. Complex stability constants (determined for some of the MnPAMs) are less indicative of the cellular fate of the complexes than the corresponding phosphate binding constants.

Redox behavior and biological properties of ferrocene bearing porphyrins.

In order to improve antimicrobial effects of previously studied meso-tetrakis(4-ferrocenylphenyl)porphyrin 1, we have modified its structure by replacing two trans-positioned ferrocenylphenyl moieties with methoxy methylene substituted tert-butylphenyl moieties. Newly synthesized 54,154-bis-(ferrocenyl)-104,204-bis-(tert-butyl)-102,106,202,206-tetrakis-(methoxy-methylene)-5,10,15,20-tetraphenylporphyrin 4 was chemically characterized in detail (by NMR, UV/Vis, IR, MALDI-TOF and ESI MS spectrometry, cyclic voltammetry, prediction of the relative lipophilicity as well as computational methods) and its biological effects were studied in terms of its antibacterial and antifungal activity (both with and without photoactivation), cytotoxicity, hemolysis and DNA cleavage. New ferrocene bearing porphyrin 4 has demonstrated a broader antimicrobial spectrum and modified effects on eukaryotic cells compared to 1. This was discussed in terms of its i) increased lipophilicity, while exhibiting lower toxicity, and ii) the redox potential of a two-electron process that is shifted to lower values, in comparison to ferrocene, thus, entering the physiologically available range and being activated towards redox interactions with biomolecules.

Pyridyl-Endcapped Polyynes: Stabilized Wire-like Molecules.

A 4-ethynylpyridyl derivative with sterically shielding phenyl groups in the 3- and 5-positions has been synthesized and used to terminate a series of polyynes. This approach allows for the synthesis of stable polyynes up to an octayne, twice as long as previous accessible for "unstabilized" pyridyl-endcapped polyynes. The potential of these polyynes as wire-like linkers to metal centers is demonstrated by axial coordination of pyridyl groups to zinc- and ruthenium-metalloporphyrins.

Reactions of Superoxide with Iron Porphyrins in the Bulk and the Near-Surface Region of Ionic Liquids.

The redox reaction of superoxide (KO2) with highly charged iron porphyrins (Fe(P4+), Fe(P8+), and Fe(P8-)) has been investigated in the ionic liquids (IL) [EMIM][Tf2N] (1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide) and [EMIM][B(CN)4] (1-ethyl-3-methylimidazolium tetracyanoborate) by using time-resolved UV/vis stopped-flow, electrochemistry, cryospray mass spectrometry, EPR, and XPS measurements. Stable KO2 solutions in [EMIM][Tf2N] can be prepared up to a 15 mM concentration and are characterized by a signal in EPR spectrum at g = 2.0039 and by the 1215 cm(-1) stretching vibration in the resonance Raman spectrum. While the negatively charged iron porphyrin Fe(P8-) does not react with superoxide in IL, Fe(P4+) and Fe(P8+) do react in a two-step process (first a reduction of the Fe(III) to the Fe(II) form, followed by the binding of superoxide to Fe(II)). In the reaction with KO2, Fe(P4+) and Fe(P8+) show similar rate constants (e.g., in the case of Fe(P4+): k1 = 18.6 ± 0.5 M(-1) s(-1) for the first reaction step, and k2 = 2.8 ± 0.1 M(-1) s(-1) for the second reaction step). Notably, these rate constants are four to five orders of magnitude lower in [EMIM][Tf2N] than in conventional solvents such as DMSO. The influence of the ionic liquid is also apparent during electrochemical experiments, where the redox potentials for the corresponding Fe(III)/Fe(II) couples are much more negative in [EMIM][Tf2N] than in DMSO. This modified redox and kinetic behavior of the positively charged iron porphyrins results from their interactions with the anions of the ionic liquid, while the nucleophilicity of the superoxide is reduced by its interactions with the cations of the ionic liquid. A negligible vapor pressure of [EMIM][B(CN)4] and a sufficient enrichment of Fe(P8+) in a close proximity to the surface enabled XPS measurements as a case study for monitoring direct changes in the electronic structure of the metal centers during redox processes in solution and at liquid/solid interfaces.

Reverse spin-crossover and high-pressure kinetics of the heme†iron center relevant for the operation of heme†proteins under deep-sea conditions.

By design of a heme model complex with a binding pocket of appropriate size and flexibility, and by elucidating its kinetics and thermodynamics under elevated pressures, some of the pressure effects are demonstrated relevant for operation of heme-proteins under deep-sea conditions. Opposite from classical paradigms of the spin-crossover and reaction kinetics, a pressure increase can cause deceleration of the small-molecule binding to the vacant coordination site of the heme-center in a confined space and stabilize a high-spin state of its Fe center. This reverse high-pressure behavior can be achieved only if the volume changes related to the conformational transformation of the cavity can offset the volume changes caused by the substrate binding. It is speculated that based on these criteria nature could make a selection of structures of heme pockets that assist in reducing metabolic activity and enzymatic side reactions under extreme pressure conditions.

Effect of ferrocene-substituted porphyrin RL-91 on Candida albicans biofilm formation.

Ferrocene-substituted porphyrin RL-91 exhibits antifungal activity against opportune human pathogen Candida albicans. RL-91 efficiently inhibits growth of both planktonic C. albicans cells and cells within biofilms without photoactivation. The minimal inhibitory concentration for plankton form (PMIC) was established to be 100 µg/mL and the same concentration killed 80% of sessile cells in the mature biofilm (SMIC80). Furthermore PMIC of RL-91 efficiently prevents C. albicans biofilm formation. RL-91 is cytotoxic for human fibroblasts in vitro in concentration of 10 µg/mL, however it does not cause hemolysis in concentrations of up to 50 µg/mL. These findings open possibility for application of RL-91 as an antifungal agent for external antibiofilm treatment of medical devices as well as a scaffold for further development of porphyrin based systemic antifungals.