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This review highlights synthesis procedures to obtain A3-, cis- and trans- A2B- and ABC-corroles. Synthesis methods from the early beginning of “corrole chemistry”, acid-catalyzed condensation methods of various building blocks (pyrrole, aldehyde, dipyrromethane, dipyrromethane-carbinol, and dipyrromethane-dicarbinol etc.), possible side reaction during Brønsted acid catalyzed reactions (scrambling), one-pot synthesis of corroles, and post-macrocyclization modification reactions of meso-substituted A3-corroles are discussed.

In this study, novel water-soluble corrole amino acid conjugates were synthesized and characterized. The coupling reaction of A2B- and A3-corroles with glycine ethyl ester and taurine under strong basic conditions proved to be successful and yielded di- and trifunctionalized corrole amino acid conjugates in good yields. The subsequent metalation of the corrole/amino acid conjugates broadens the scope for applications considerably. As examples, we herein show the catalytic activity of the Mn(III) A3-corrole towards O2 evolution. First we employed tert-butyl hydroperoxide (t-BuOOH) as oxidant to obtain the Mn(V)oxo species and tetrabutyl ammonium hydroxide (TBAH) as hydroxide donor agent. Furthermore, the binding properties of the non-metalated and the Mn(III) A3-corrole/amino sulfonic acid conjugates and transport of proteins were investigated and the conjugates exhibited binding to human serum albumin (HSA). Finally, a novel Ga(III) A3-corrole/amino sulfonic acid derivative was synthesized and we briefly describe the photophysical properties of this compound. Copyright © 2013 John Wiley & Sons, Ltd.

The BiIII ion in the center of the corrole macrocyclic ring system was employed to stabilize and protect the corrole inner core during the functionalization at the periphery (meso positions) of the π-conjugated ring system. Moreover, the ease of demetalation makes BiIII–corroles attractive candidates for functionalization and subsequent demetalation to the free-base corroles. Herein we present examples of possible derivatization reactions of Bi–corroles by employing Suzuki cross-coupling under gentle conditions at ambient temperature. This high-yielding methodology facilitates the design of A2B corroles that bear elaborate subunits such as the indolyl and pyrenyl group, which are difficult to realize with the synthetic protocols available to date. Later, Pd-catalyzed C–N coupling reactions with the same precursor were tested. To make the corresponding free-base corroles also accessible by means of these new routes, a versatile procedure was developed that allows the subsequent demetalation of the obtained Bi–corroles. Electrochemical characterization was performed with cyclic voltammetry and spectroelectrochemistry to clarify the ring-centred oxidation and reduction processes. Structural considerations of the dome-shaped nature of Bi–corrole derivatives are presented and corroborated by 19F NMR spectroscopy as well as quantum chemical calculations.

d-Amino acids in peptide linkage are a noteworthy exception from the universal homochirality of proteins and peptides.[1] The first animal peptide that was found to contain a d-amino acid as the second residue was dermorphin, isolated from the skin of a South American tree frog.[2] This peptide binds with high affinity to μ-opiate receptors. The d-residue in this and related amphibian opioid peptides is essential for the biological function, whereas the all-L-isomers lack activity.

An efficient metalation procedure for bismuth complexes with meso-substituted corrole ligands is presented. Reaction of 5,10,15-tris-pentafluorophenylcorrole H(3)(TpFPC) with Bi{N(SiMe(3))(3)} converts the free ligand H(3)(TpFPC) to a neutral low-valent species Bi(TpFPC), which has been characterized by different spectroscopic techniques. (Spectro)electrochemical studies were performed in order to describe the redox potentials of the Bi(TpFPC) complex and to ascribe the sites of electron transfer. The first crystal structure of a bismuth corrole is presented and compared to the geometry-optimized molecular structure obtained with density functional theory (DFT) calculations. We show an example of a 4-coordinate metallocorrole with a very large out-of-plane displacement and significant doming. The electronic structure of the novel bismuth corrole system is discussed in detail. Time-dependent DFT results support the proposed assignment of electronic transitions observed for the Bi(TpFPC) derivative. To account for the reactivity we investigated the photocatalytic properties of the Bi(TpFPC) complex.

A constant-time TOCSY difference experiment for the determination of (3)J((1)H3'-(31)P) coupling constants in non-isotope-labelled DNA oligonucleotides is presented. The method is tested on a DNA octamer and compared with the established constant-time NOESY difference method. Each (3)J((1)H3'-(31)P) coupling constant is determined from amplitude changes caused by phosphorous decoupling, which are observable on multiple cross-peaks, thus leading to a high accuracy of the value of the (3)J((1)H3'-(31)P) coupling constant. The new experiment delivers up to three times the sensitivity compared with previously reported methods.

The first examples of bismuth complexes with meso-substituted corrole ligands are presented. Complexation of 5,10,15-triphenylcorrole with bismuth(III) salts leads to the formation of a neutral low-valent species Bi-tpc, which is characterized by various spectroscopic techniques. In addition to the intense intraligand (IL) absorption bands of the corrole macrocycle, this bismuth(III) complex displays metal-centered (MC) sp -transitions and metal-to-ligand charge transfer (MLCT) transitions which show a substantial mixing with the intraligand absorption bands, thus resulting in an irregular hyper -type electronic spectrum. Excitation of Bi-tpc in the spectral region of the MC-bands under ambient conditions leads to dioxygen activation and concomitant photochemical formation of the high-valent species (O )Bi V (tpc), an unprecedented example of a bismuth(V) tetrapyrrole complex. As a potential reaction intermediate of this photoredox process, a labile hydroperoxo species (HOO)Bi V (tpc) + is also identified. First results on the spectroscopic features and the chemical reactivity of (O )Bi V (tpc) are reported. In solution this neutral bismuth(V) species is in equilibrium with the corresponding protonated form (HO)Bi V (tpc) + carrying an axial hydroxo ligand. Axial ligand exchange processes and the formation of adducts with solvent derived photoproducts are also identified in high-resolution mass spectra of irradiated samples. The molecular and electronic structures of the novel bismuth corrole systems are discussed in terms of supporting density functional theory (DFT) calculations, which suggest an out-of-plane structure of the Bi-tpc and (O )Bi V (tpc) species. Time-dependent DFT results are supporting the proposed assignment of electronic transitions observed in low- and high-valent bismuth tpc derivatives.

The palladium-catalyzed Suzuki–Miyaura cross-coupling reaction has been investigated on meso-substituted trans-A2B-corrole using tailored Pd-catalyst systems. We present the first examples of Suzuki–Miyaura cross-coupling reactions on meso-substituted trans-A2B-corrole derivatives with neutral, sterically hindered, inactivated and heteroaromatic boronic acids and esters, alkenylboronic acids, as well as quickly deboronating aryl boronic acids and benzo-condensated five membered heterocyclic boronic acids. In addition, we established a high-yield procedure for the Suzuki–Miyaura cross-coupling reaction of corroles with neutral boronic acids. Due to the lability of the free-base corrole macrocycles, functionalization of the corrole periphery was performed with the corresponding Cu-metallated species. meso-Substituted trans-A2B-corrole can hence be regarded as highly versatile platform towards more sophisticated corrole systems. X-ray structure analysis of a functionalized meso-substituted trans-A2B copper corrole exhibited the typical features of such a Cu-complex: short N–Cu distances and a saddled corrole configuration. Moreover, we observed a sensitivity of the formal oxidation state of the coordinated copper ions towards Suzuki–Miyaura cross-coupling reaction conditions, where the central copper(III) ion approaches the characteristic features of a copper(II) species. This redox behaviour was examined by UV/vis absorption spectra, nuclear magnetic resonance (NMR) experiments and time-dependent density functional theoretical calculations., Graphical abstract

The first observation of Pb(II)-complexes of corroles and their photoinduced oxidation to the corresponding Pb(IV)-derivatives is reported. These compounds display metal-centered redox chemistry in solution. Their potential for catalytic oxygen atom transfer processes is explored.

The novel gold porphyrin complex (5,10,15-tris(N-methylpyridinium-4-yl)-20-(1-pyrenyl)-porphyrinato)gold(III) chloride, [Au(III)(TMPy3Pyr1P)]Cl4, was prepared and characterized by optical spectroscopy, high-resolution nuclear magnetic resonance (NMR), and electrospray mass spectrometry. This cationic multichromophore compound exhibits excellent water solubility and does not form aggregates under physiological conditions. Binding interactions of this complex and related model compounds with nucleic acid substrates have been studied and characterized by NMR and circular dichroism spectroscopy. The photoreactivity of [Au(III)(TMPy3Pyr1P)]Cl4 was investigated under anaerobic and aerobic conditions in the presence of an excess of purine nucleoside, guanosine, and plasmid DNA. Photocatalytic oxidative degradation of guanosine and the change from supercoiled to circular plasmid DNA upon monochromatic irradiation and polychromatic blue-light exposure with a maximum at 420 nm was explored. The potential of the novel water-soluble cationic metallointercalator complex [Au(III)(TMPy3Pyr1P)]Cl4 to serve as a catalytic photonuclease for the cleavage of DNA has been demonstrated.

Photophysical and photochemical characterization of a novel cationic silicon phthalocyanine with excellent water solubility properties is reported. The robust red-light responsive compound shows very attractive features as a sensitizer for reductive and oxidative quenching processes to trigger photocatalytic substrate conversion in aqueous solution.

Low-temperature scanning tunneling microscopy, a well-established technique for single-molecule investigations in an ultrahigh vacuum environment, has been used to study the electronic properties of Au(III) 5,10,15,20-tetraphenylporphyrin (AuTPP) molecules on Au(111) at the submolecular scale. AuTPP serves as a model system for chemotherapeutically relevant Au(III) porphyrins. For the first time, real-space images and local scanning tunneling spectroscopy data of the frontier molecular orbitals of AuTPP are presented. A comparison with results from density functional theory reveals significant deviations from gas-phase behavior due to a non-negligible molecule/substrate interaction. We identify the oxidation state of the central metal ion in the adsorbed AuTPP as Au(3+).

In this study we demonstrate anticancer activity of novel fully water soluble cationic porphyrins. The two cationic porphyrins 5,10,15- tris ( N -methylpyridinium-4-yl)-20-[1-phenyl-4-(3- N -phenylsulfonylindolyl)]-21 H ,23 H -porphyrin chloride (TMPy 3 PhenIndolprot 1 P–Cl 3 ) and 5-{5-[2-(9,9-Dimethyl)fluorenyl]- N -methylpyridinium-3-yl}-10,15,20-tris( N -methyl-pyridinium-4-yl)-21 H ,23 H -porphyrin chloride (TMPy 3 PyFluorenyl 1 P–Cl 4 ) were prepared and their antiproliferative effects were studied in two human tumor cell lines and a normal human fibroblast cell line. Effects of the novel porphyrin compounds were evaluated in the small intestinal neuroendocrine tumor cell line KRJ-I, the medullary thyroid carcinoma cell line MTC-SK and the normal human fibroblast cell line HF-SAR by cell counting, cell proliferation assays and cell cytotoxicity analyses. TMPy 3 PhenIndolprot 1 P–Cl 3 and TMPy 3 PyFluorenyl 1 P–Cl 4 showed antiproliferative effects in the tumor cell lines MTC-SK and KRJ-I; cell viability was decreased and cytotoxic effects were quantified, while no significant alterations of the human fibroblasts were noted. With the advantage of full water solubility and antiproliferative effects in tumor cell lines, the novel porphyrin compounds TMPy 3 PhenIndolprot 1 P–Cl 3 and TMPy 3 PyFluorenyl 1 P–Cl 4 could be a new therapeutic option in anticancer treatment.

Graphical abstract Highlights ► Synthesis of tri-cationic porphyrin–EDTA conjugate (TMPy3PhenEDTA-P-Cl4). ► Treatment of small-intestinal neuroendocrine tumor cells with TMPy3PhenEDTA-P-Cl4. ► Treatment of medullary thyroid carcinoma cell lines with TMPy3PhenEDTA-P-Cl4. ► Apoptotic cell death on MTC cells after treatment with TMPy3PhenEDTA-P-Cl4., In this study, a completely water soluble tri-cationic porphyrin–EDTA conjugate was synthesized. We present data demonstrating the tumoristatic effects of the novel fully water soluble cationic porphyrin TMPy3PhenEDTA-P-Cl4 in the dark, in the medullary thyroid carcinoma cell lines MTC-SK and SHER-I and weaker effects in the small intestinal neuroendocrine tumor cell line KRJ-I. In addition, cytotoxic effects were also studied in normal human fibroblasts that represent normal tissue and the results are compared to the tumor cell lines.

Candida albicans is one of the most common pathogens of humans. One important virulence factor of C. albicans is its ability to form elongated hyphae that can invade host tissues and cause disseminated infections. Here, we show the effect of different physiologically relevant temperatures and common antifungal drugs on the growth and mechanical properties of C. albicans hyphae using atomic force microscopy. We demonstrate that minor temperature fluctuations within the normal range can have profound effects on hyphal cell growth and that different antifungal drugs impact hyphal cell stiffness and adhesion in different ways., Candida albicans is an opportunistic fungal pathogen of humans known for its ability to cause a wide range of infections. One major virulence factor of C. albicans is its ability to form hyphae that can invade host tissues and cause disseminated infections. Here, we introduce a method based on atomic force microscopy to investigate C. albicans hyphae in situ on silicone elastomer substrates, focusing on the effects of temperature and antifungal drugs. Hyphal growth rates differ significantly for measurements performed at different physiologically relevant temperatures. Furthermore, it is found that fluconazole is more effective than caspofungin in suppressing hyphal growth. We also investigate the effects of antifungal drugs on the mechanical properties of hyphal cells. An increase in Young’s modulus and a decrease in adhesion force are observed in hyphal cells subjected to caspofungin treatment. Young’s moduli are not significantly affected following treatment with fluconazole; the adhesion force, however, increases. Overall, our results provide a direct means of observing the effects of environmental factors and antifungal drugs on C. albicans hyphal growth and mechanics with high spatial resolution. IMPORTANCE Candida albicans is one of the most common pathogens of humans. One important virulence factor of C. albicans is its ability to form elongated hyphae that can invade host tissues and cause disseminated infections. Here, we show the effect of different physiologically relevant temperatures and common antifungal drugs on the growth and mechanical properties of C. albicans hyphae using atomic force microscopy. We demonstrate that minor temperature fluctuations within the normal range can have profound effects on hyphal cell growth and that different antifungal drugs impact hyphal cell stiffness and adhesion in different ways.

Candida albicans is a commensal as well as a pathogen of humans. C. albicans is able to mount a cellular response to a diverse range of external stimuli in the host and switch reversibly between the yeast and hyphal growth forms. Hyphal development is a key virulence determinant. Here, we studied how C. albicans senses different environmental signals to control its growth forms. Our study results suggest that robust hyphal development requires downregulation of two transcriptional repressors, Nrg1 and Sfl1. Acidic pH or cationic stress inhibits hyphal formation via stress-responsive kinases and Sfl1., Candida albicans is an important human pathogen responsible for causing both superficial and systemic infections. Its ability to switch from the yeast form to the hyphal growth form is required for its pathogenicity. Acidic pH inhibits hyphal initiation, but the nature of the mechanism for this inhibition is not completely clear. We show that acidic pH represses hyphal initiation independently of the temperature- and farnesol-mediated Nrg1 downregulation. Using a collection of transcription factor deletion mutants, we observed that the sfl1 mutant induced hyphae in acidic pH but not in farnesol at 37°C. Furthermore, transcription of hyphal regulators BRG1 and UME6 was not induced in wild-type (WT) cells but was induced in the sfl1 mutant during hyphal induction in acidic pH. Using the same screening conditions with the collection of kinase mutants, we found that deletions of the core stress response mitogen-activated protein (MAP) kinase HOG1 and its kinase PBS2, the cell wall stress MAP kinase MKC1, and the calcium/calmodulin-dependent kinase CMK1 allowed hyphal initiation in acidic pH. Furthermore, Hog1 phosphorylation induced by high osmotic stress also retarded hyphal initiation, and the effect was abolished in the sfl1 and three kinase mutants but was enhanced in the phosphatase mutant ptp2 ptp3. We also found functional associations among Cmk1, Hog1, and Sfl1 for cation stress. Our study results suggest that robust hyphal initiation requires downregulation of both Nrg1 and Sfl1 transcriptional repressors as well as timely BRG1 expression. Acidic pH and cationic stress retard hyphal initiation via the stress-responsive kinases and Sfl1. IMPORTANCE Candida albicans is a commensal as well as a pathogen of humans. C. albicans is able to mount a cellular response to a diverse range of external stimuli in the host and switch reversibly between the yeast and hyphal growth forms. Hyphal development is a key virulence determinant. Here, we studied how C. albicans senses different environmental signals to control its growth forms. Our study results suggest that robust hyphal development requires downregulation of two transcriptional repressors, Nrg1 and Sfl1. Acidic pH or cationic stress inhibits hyphal formation via stress-responsive kinases and Sfl1.

Adaptation to alternating CO2 concentrations is crucial for all organisms. Carbonic anhydrases—metalloenzymes that have been found in all domains of life—enable fixation of scarce CO2 by accelerating its conversion to bicarbonate and ensure maintenance of cellular metabolism. In fungi and other eukaryotes, the carbonic anhydrase Nce103 has been shown to be essential for growth in air (~0.04% CO2). Expression of NCE103 is regulated in response to CO2 availability. In Saccharomyces cerevisiae, NCE103 is activated by the transcription factor ScCst6, and in Candida albicans and Candida glabrata, it is activated by its homologues CaRca1 and CgRca1, respectively. To identify the kinase controlling Cst6/Rca1, we screened an S. cerevisiae kinase/phosphatase mutant library for the ability to regulate NCE103 in a CO2-dependent manner. We identified ScSch9 as a potential ScCst6-specific kinase, as the sch9Δ mutant strain showed deregulated NCE103 expression on the RNA and protein levels. Immunoprecipitation revealed the binding capabilities of both proteins, and detection of ScCst6 phosphorylation by ScSch9 in vitro confirmed Sch9 as the Cst6 kinase. We could show that CO2-dependent activation of Sch9, which is part of a kinase cascade, is mediated by lipid/Pkh1/2 signaling but not TORC1. Finally, we tested conservation of the identified regulatory cascade in the pathogenic yeast species C. albicans and C. glabrata. Deletion of SCH9 homologues of both species impaired CO2-dependent regulation of NCE103 expression, which indicates a conservation of the CO2 adaptation mechanism among yeasts. Thus, Sch9 is a Cst6/Rca1 kinase that links CO2 adaptation to lipid signaling via Pkh1/2 in fungi., IMPORTANCE All living organisms have to cope with alternating CO2 concentrations as CO2 levels range from very low in the atmosphere (0.04%) to high (5% and more) in other niches, including the human body. In fungi, CO2 is sensed via two pathways. The first regulates virulence in pathogenic yeast by direct activation of adenylyl cyclase. The second pathway, although playing a fundamental role in fungal metabolism, is much less understood. Here the transcription factor Cst6/Rca1 controls carbon homeostasis by regulating carbonic anhydrase expression. Upstream signaling in this pathway remains elusive. We identify Sch9 as the kinase controlling Cst6/Rca1 activity in yeast and demonstrate that this pathway is conserved in pathogenic yeast species, which highlights identified key players as potential pharmacological targets. Furthermore, we provide a direct link between adaptation to changing CO2 conditions and lipid/Pkh1/2 signaling in yeast, thus establishing a new signaling cascade central to metabolic adaptation.