Tetrapyrrolic Macrocycles: Synthesis, Functionalization and Applications 2018.

Natural and synthetic macrocycles like porphyrins, corroles and phthalocyanines are considered strong candidates to be used in different fields, such as catalysis, sensing, medicine, materials science, or in the development of advanced biomimetic models. All these applications are strongly dependent on the availability of compounds with adequate and specific structural features. This Special Issue has collected 13 contributions which consolidate and expand our knowledge on the application of these macrocycles in different fields accompanied by innovative synthetic methodologies to afford and to functionalize this type of compounds.

Recent Advances in Catalyzed Sequential Reactions and the Potential Use of Tetrapyrrolic Macrocycles as Catalysts.

Complexes of porphyrins and of other similar tetrapyrrolic macrocycles are extensively explored as catalysts for different chemical processes, and the development of solid catalysts for heterogeneous processes using molecules with the ability to act as multifunctional catalysts in one-pot reactions is increasing and can lead to the wider use of this class of molecules as catalysts. This mini review focuses on the application of this class of complexes as catalysts in a variety of sequential one-pot reactions.

Electron Transfer and Geometric Conversion of Co-NO Moiety in Saddled Porphyrins: Implications for Trigger Role of Tetrapyrrole Distortion.

The electrons of NO and Co are strongly delocalized in normal {Co-NO}8 species. In this work, {Co-NO}8 complexes are induced to convert from (CoII)+•-NO• to CoIII-NO- by a core contraction of 0.06 Šin saddled cobalt(II) porphyrins. This intramolecular electron transfer mechanism indicates that nonplanarity of porphyrin is involved in driving conversion of the NO units from electrophilic NO• as a bent geometry to nucleophilic NO- as a linear geometry. This implies that distortion acts as a trigger in enzymes containing tetrapyrrole. The electronic behaviors of the CoII ions and Co-NO moieties were confirmed by X-ray crystallography, EPR spectroscopy, theoretical calculation, UV-vis and IR spectroscopy, and electrochemistry.

Nucleophilic Aromatic Substitution on Pentafluorophenyl-Substituted Dipyrranes and Tetrapyrroles as a Route to Multifunctionalized Chromophores for Potential Application in Photodynamic Therapy.

The application of porphyrinoids in biomedical fields, such as photodynamic therapy (PDT), requires the introduction of functional groups to tune their solubility for the biological environment and to allow a coupling to other active moieties or carrier systems. A valuable motif in this regard is the pentafluorophenyl (PFP) substituent, which can easily undergo a regiospecific nucleophilic replacement (SN Ar) of its para-fluorine atom by a number of nucleophiles. Here, it is shown that, instead of amino-substitution on the final porphyrinoid or BODIPY (boron dipyrromethene), the precursor 5-(PFP)-dipyrrane can be modified with amines (or alcohols). These dipyrranes were transformed into amino-substituted BODIPYs. Condensation of these dipyrranes with aldehydes gave access to trans-A2 B2 -porphyrins and trans-A2 B-corroles. By using pentafluorobenzaldehyde, it was possible to introduce another para-fluorine atom, which enabled the synthesis of multifunctionalized tetrapyrroles. Furthermore, alkoxy- and amino-substituted dipyrranes were applied to the synthesis of A3 B3 -hexaphyrins. The polar porphyrins that were prepared by using this method exhibited in vitro PDT activity against several tumor cell lines.

Synthesis of SF5-Substituted Tetrapyrroles, Metalloporphyrins, BODIPYs, and Their Dipyrrane Precursors.

The synthesis of novel pentafluorosulfanyl (SF5)-substituted A4-type porphyrins, their corresponding Zn(II)- and Pd(II)-metal complexes, A3-, A2B- and AB2-type corroles, BODIPYs, and their dipyrrane precursors was studied utilizing commercially available SF5-substituted aryl aldehydes. In addition, the functionalization of SF5-substituted tetrapyrroles was investigated by applying the concept of the nucleophilic aromatic substitution (S(N)Ar) with alcohols and sodium azide onto the pentafluorophenyl moiety of a trans-A2B2-porphyrin and two corrole derivatives with a mixed substitution pattern involving the SF5 group. This allows a fine-tuning of the properties of these macrocycles through a selective and mild introduction of functional groups, giving access to multifunctionalized SF5-substituted porphyrinoids. As an example, one functionalized corrole was further reacted with an azido-substituted BODIPY via the copper(I)-catalyzed 1,3-dipolar cycloaddition yielding the first corrole-BODIPY heterodimer involving the pentafluorosulfanyl group.

Crossed and linked histories of tetrapyrrolic macrocycles and their use for engineering pores within sol-gel matrices.

The crossed and linked histories of tetrapyrrolic macrocycles, interwoven with new research discoveries, suggest that Nature has found in these structures a way to ensure the continuity of life. For diverse applications porphyrins or phthalocyanines must be trapped inside solid networks, but due to their nature, these compounds cannot be introduced by thermal diffusion; the sol-gel method makes possible this insertion through a soft chemical process. The methodologies for trapping or bonding macrocycles inside pristine or organo-modified silica or inside ZrO2 xerogels were developed by using phthalocyanines and porphyrins as molecular probes. The sizes of the pores formed depend on the structure, the cation nature, and the identities and positions of peripheral substituents of the macrocycle. The interactions of the macrocyclic molecule and surface Si-OH groups inhibit the efficient displaying of the macrocycle properties and to avoid this undesirable event, strategies such as situating the macrocycle far from the pore walls or to exchange the Si-OH species by alkyl or aryl groups have been proposed. Spectroscopic properties are better preserved when long unions are established between the macrocycle and the pore walls, or when oligomeric macrocyclic species are trapped inside each pore. When macrocycles are trapped inside organo-modified silica, their properties result similar to those displayed in solution and their intensities depend on the length of the alkyl chain attached to the matrix. These results support the prospect of tuning up the pore size, surface area, and polarity inside the pore cavities in order to prepare efficient catalytic, optical, sensoring, and medical systems. The most important feature is that research would confirm again that tetrapyrrolic macrocycles can help in the development of the authentic pore engineering in materials science.

Primordial oil slick and the formation of hydrophobic tetrapyrrole macrocycles.

The functional end products of the extant biosynthesis of tetrapyrrole macrocycles in photosynthetic organisms are hydrophobic: chlorophylls and bacteriochlorophylls. A model for the possible prebiogenesis of hydrophobic analogues of nature's photosynthetic pigments was investigated by reaction of acyclic reactants in five media: aqueous solution (pH 7, 60°C, 24 h); aqueous solution containing 0.1 M decanoic acid (which forms a turbid suspension of vesicles); or aqueous solution accompanied by dodecane, mesitylene, or a five-component organic mixture (each of which forms a phase-separated organic layer). The organic mixture was composed of equimolar quantities of decanoic acid, dodecane, mesitylene, naphthalene, and pentyl acetate. The reaction of 1,5-dimethoxy-3-methylpentan-2,4-dione and 1-aminobutan-2-one to give etioporphyrinogens was enhanced in the presence of decanoic acid, affording (following chemical oxidation) etioporphyrins (tetraethyltetramethylporphyrins) in yields of 1.4-10.8% across the concentration range of 3.75-120 mM. The yield of etioporphyrins was greater in the presence of the five-component organic mixture (6.6% at 120 mM) versus that with dodecane or mesitylene (2.1% or 2.9%, respectively). The reaction in aqueous solution with no added oil-slick constituents resulted in phase separation-where the organic reactants themselves form an upper organic layer-and the yield of etioporphyrins was 0.5-2.6%. Analogous reactions leading to uroporphyrins (hydrophilic, eight carboxylic acids) or coproporphyrins (four carboxylic acids) were unaffected by the presence of decanoic acid or dodecane, and all yields were at most ∼2% or ∼8%, respectively. Taken together, the results indicate a facile means for the formation of highly hydrophobic constituents of potential value for prebiotic photosynthesis.

A strategy for the targeting of photosensitizers. Synthesis, characterization, and photobiological property of porphyrins bearing glycodendrimeric moieties.

This paper describes the conception, synthesis, and characterization of new tetrapyrrolic chromophores bearing glycodendrimeric moieties inducing a potential increase of tumor targeting by a cluster effect. Two families of monoglycodendrimeric photosensitizers bearing three glycosyl units were designed, prepared with an acceptable overall efficiency and characterized by NMR, UV-visible, and fluorescence spectroscopies. The polarity and log P were evaluated by HPLC and the stir-flask method, respectively. The in vitro photoefficiency against two human tumor cell lines was assessed. The presence of the glycodendrimeric group does not appear to increase the tumor in vitro targeting.

Synthesis and characterization of new porphyrazine-Gd(III) conjugates as multimodal MR contrast agents.

Magnetic resonance imaging (MRI) has long been used clinically and experimentally as a diagnostic tool to obtain three-dimensional, high-resolution images of deep tissues. These images are enhanced by the administration of contrast agents such as paramagnetic Gd(III) complexes. Herein, we describe the preparation of a series of multimodal imaging agents in which paramagnetic Gd(III) complexes are conjugated to a fluorescent tetrapyrrole, namely, a porphyrazine (pz). Zinc metalated pzs conjugated to one, four, or eight paramagnetic Gd(III) complexes are reported. Among these conjugates, Zn-Pz-8Gd(III) exhibits an ionic relaxivity four times that of the monomeric Gd(III) agent, presumably because of increased molecular weight and a molecular relaxivity that is approximately thirty times larger, while retaining the intense electronic absorption and emission of the unmodified pz. Unlike current clinical MR agents, Zn-Pz-1Gd(III) is taken up by cells. This probe demonstrates intracellular fluorescence by confocal microscopy and provides significant contrast enhancement in MR images, as well as marked phototoxicity in assays of cellular viability. These results suggest that pz agents possess a new potential for use in cancer imaging by both MRI and near-infrared (NIR) fluorescence, while acting as a platform for photodynamic therapy.

The role of the chromophore in the biological photoreceptor phytochrome: an approach using chemically synthesized tetrapyrroles.

In plants and bacteria, phytochromes serve as light-inducible, red-/far-red light sensitive photoreceptors that control a wide range of photomorphogenetic processes. Phytochromes comprise a protein moiety and a covalently bound bilin chromophore. Bilins are open-chain tetrapyrrole compounds that derive biosynthetically from ubiquitous porphyrins. The investigations of phytochromes reveal that precise interactions between the protein moiety and its bilin chromophore are essential for the proper functioning of this photoreceptor; accordingly, synthetic manipulation of the parts is an important method for studying the whole. Although variations in the protein structure are readily accomplished by routine mutagenesis protocols, the generation of structurally modified bilins is a laborious, multistep process. Recent improvement in the synthesis of open-chain tetrapyrroles now permits the generation of novel, structurally modified (and even selectively isotope-labeled) chromophores. Furthermore, by using the capability of recombinant apo-phytochrome to bind the chromophore autocatalytically, researchers can now generate novel chromoproteins with modified functions. In the protein-bound state, the phytochrome chromophore is photoisomerized at one double bond, in the bridge between the last two of the four pyrrole rings (the C and D rings), generating the thermally stable, physiologically active P(fr) form. This conversion--photoisomerization from the form absorbing red light (P(r)) to the form absorbing far-red light (P(fr))--covers 12 orders of magnitude, from subpicoseconds to seconds. Such spectroscopic and kinetic studies yield a wealth of time-resolved spectral data, even more so, if proteins with changed sequence or chromophore structure are utilized. In particular, bilins with a changed substitution pattern at the photoisomerizing ring D have shed light on the chromophore-protein interactions during the photoisomerization. The mechanisms generating and stabilizing the light-induced P(fr) form of phytochromes are now seen in greater detail. On the other hand, the use of bilins with selective incorporation of stable isotopes identify light-induced conformational motions when studied by vibrational (FTIR and Raman) and NMR spectroscopy. In this Account, we present spectroscopic investigations that provide structural details in these biological photoreceptors with great precision and document the dynamics elicited by light excitation. This approach yields important information that complements the data deduced from crystal structure.

The use of synthetic linear tetrapyrroles to probe the verdin sites of human biliverdin-IXalpha reductase and human biliverdin-IXbeta reductase.

Many vertebrate species express two enzymes that are capable of catalysing the reduction of various isomers of biliverdin. Biliverdin-IXalpha reductase (BVR-A) is most active with its physiological substrate biliverdin-IXalpha, but can also reduce the three other biliverdin isomers IXbeta, IXdelta and IXgamma. Biliverdin-IXbeta reductase (BVR-B) catalyses the reduction of only the IXbeta, IXdelta and IXgamma isomers of biliverdin. Therefore, the activity of BVR-A can be measured using biliverdin-IXalpha as a specific substrate. We now show that the dimethyl esters of biliverdin-IXbeta and biliverdin-IXdelta are substrates for BVR-B, but not for BVR-A. This provides a useful method for specifically assaying the activity of both BVR-A and BVR-B in crude mixtures, using biliverdin-IXalpha for BVR-A and the dimethyl ester of either biliverdin-IXbeta or biliverdin-IXdelta for BVR-B. Human BVR-A has been suggested as a pharmacological target for neonatal jaundice. Because of the absence of a crystal structure with biliverdin bound to BVR-A, we have investigated indirect ways of examining tetrapyrrole binding. In the present study, we report that a number of sterically locked conformers of 18-ethylbiliverdin-IXalpha are substrates for human BVR-A, and discuss the implications for the biliverdin binding site. The oxidation of bilirubin-IXalpha ditaurate to biliverdin-IXalpha ditaurate is also described. We show that biliverdin-IXalpha ditaurate is a substrate for human BVR-A and discuss the possibility of using a competing substrate, which is reduced to a water soluble and excretable rubin, as a prototypic inhibitor of BVR-A.

New open-chain tetrapyrroles as chromophores in the plant photoreceptor phytochrome.

A series of six open-chain tetrapyrroles has been synthesized and used as chromophores for the plant photoreceptor protein phytochrome. The novel chromophores vary in the size of substituents 17 and 18 at ring D. This ring undergoes maximal conformational change upon light excitation ( Z --> E photoisomerization of the 15,16-double bond). Instead of methyl and vinyl substituents (positions 17, 18) as present in the native chromophore phytochromobilin, dimethyl, methyl and isopropyl, methyl and tert-butyl, ethyl and methyl, vinyl and methyl, and isopropyl and methyl substituents have been generated. All novel chromophores assemble with the apoprotein. The obtained chromoproteins show hypsochromic shifts of the absorbance maxima by 10 nm maximally, compared to the native pigment, except for the 17-isopropyl-18-methyl-substituted compound which showed a 100 nm hypsochromic shift of selectively the P r form. The assembly kinetics were slowed down in correlation to the increasing size of the substituents, with stronger effects for modified substituents at position 17. The thermal stability of the photoinduced P fr form for the 18-isopropyl and the 18- tert butyl substituents was even greater than that of the native pigments. Those chromophores carrying substituents at position 17 larger than the methyl group (ethyl and isopropyl) showed a very low stability of the respective P fr forms. Time-resolved detection of the P r to P fr conversion (laser-induced flash photolysis) revealed a slower formation of the P fr form for those chromophores carrying larger substituents at position 18, whereas the rise and decay kinetics of the early intermediates are only moderately changed. Introduction of larger substituents at position 17 (ethyl, vinyl, and isopropyl) causes drastic changes in the kinetics; in particular the formation of the first thermally stable intermediate, I 700, is significantly slowed, making a detection of its rise possible.

Toward a general synthesis of chlorins.

Recently, we described a new synthesis of C,D-ring symmetric chlorins 11, involving 2 + 2 condensation of bis-formyl-dihydrodipyrrins 9 with symmetrically substituted dipyrromethane diacids 10 (Method I). However, while versatile in many aspects, Method I was unsuited to the broader goal of synthesizing fully non-symmetric chlorins of general structure 15, which requires regioselective control over the reacting centers in the A,B- and C,D-ring components. In this paper, we describe four new 2 + 2 strategies that accomplish this differentiation (Methods II-V). Of these, Method V, which combines operational simplicity with moderate to high product yields, proved to be the most effective route, exploiting reactivity differences between the two formyl groups of A,B-rings 9 to impart excellent regioselectivity. Methods II-IV are also useful alternatives to Method V, although in some cases, the appropriately functionalized precursors are less readily available. All four approaches generate single regioisomers of diversely substituted chlorins, and in every case, the 2 + 2 condensation is accomplished in a simple, one-flask procedure without need for additives such as oxidizing agents or metals. Taken together, these methodologies provide expanded access to an array of chlorins for SAR studies that may advance the effectiveness of PDT and other applications.

Preparation and in vitro biological evaluation of tetrapyrrole ethanolamide derivatives as potential anticancer agents.

Tetrapyrrole ethanolamide derivatives, 1 and 2, were prepared from hematoporphyrin IX (HPIX, 3) and methyl pheophorbide a (mPheo, 6). These were evaluated for their dual action as chemotherapeutics and photosensitizers in treatment of cancer. The novel compounds showed significant in vitro anticancer activity as measured in different cell lines using the MTT assay and photodynamic activity measured by erythrocytes' photohemolysis.