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1.  Synthesis of 3,8-Dichloro-6-ethyl-1,2,5,7-tetramethyl–BODIPY from an Asymmetric Dipyrroketone and Reactivity Studies at the 3,5,8-Positions** 
The asymmetric BODIPY 1a (BODIPY=4,4-difluoro-4-bora-3a,4a-diaza-s-indacene), containing two chloro substituents at the 3,8-positions and a reactive 5-methyl group, was synthesized from the asymmetric dipyrroketone 3, which was readily obtained from available pyrrole 2a. The reactivity of 3,8-dichloro-6-ethyl-1,2,5,7-tetramethyl-BODIPY 1a was investigated by using four types of reactions. This versatile BODIPY undergoes regioselective Pd0-catalyzed Stille coupling reactions and/or regioselective nucleophilic addition/elimination reactions, first at the 8-chloro and then at the 3-chloro group, using a variety of organostannanes and N-, O-, and S-centered nucleophiles. On the other hand, the more reactive 5-methyl group undergoes regioselective Knoevenagel condensation with an aryl aldehyde to produce a monostyryl-BODIPY, and oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) gives the corresponding 5-formyl-BODIPY. Investigation of the reactivity of asymmetric BODIPY 1a led to the preparation of a variety of functionalized BODIPYs with λmax of absorption and emission in the ranges 487–587 and 521–617 nm, respectively. The longest absorbing/emitting compound was the monostyryl-BODIPY 16, and the largest Stokes shift (49 nm) and fluorescence quantum yield (0.94) were measured for 5-thienyl-8-phenoxy-BODIPY 15. The structural properties (including 16 X-ray structures) of the new series of BODIPYs were investigated.
PMCID: PMC4382426  PMID: 25761150
addition/elimination; BODIPY; fluorescence; Pd0-catalyzed coupling; oxidation; substitution
2.  Functionalization of 3,5,8-Trichlorinated BODIPY Dyes 
The Journal of organic chemistry  2014;79(21):10342-10352.
Catalytic hydrogenation of dibenzyl 5-dipyrroketone-2,9-dicarboxylates followed by decarboxylative iodination affords a 2,9-diiododipyrroketone which gives a 2,5,9-trichlorodipyrromethene hydrochloride after nucleophilic addition/elimination, with adventitious chloride to replace the two iodide groups. Treatment with BF3·Et2O gives a 3,5,8-trichloro-BODIPY that readily undergoes regioselective Stille coupling at the 8-position, or homo/mixed couplings at the 3,8- or 3,5- and 8-positions. Stepwise and controlled replacement of the 3,5- and 8-chlorine atoms using Stille reagents results in formation of a completely unsymmetrical trisubstituted BODIPY. Several examples of unsymmetrical BODIPYs were synthesized and characterized using this methodology. Structure features of new BODIPYs are discussed within the context of 14 new X-ray structures, and photophysical parameters of all new BODIPY compounds are reported and discussed.
PMCID: PMC4227577  PMID: 25268574
3.  Functionalization of 3,5,8-Trichlorinated BODIPY Dyes 
The Journal of Organic Chemistry  2014;79(21):10342-10352.
Catalytic hydrogenation of dibenzyl 5-dipyrroketone-2,9-dicarboxylates followed by decarboxylative iodination affords a 2,9-diiododipyrroketone which gives a 2,5,9-trichlorodipyrromethene hydrochloride after nucleophilic addition/elimination, with adventitious chloride to replace the two iodide groups. Treatment with BF3·Et2O gives a 3,5,8-trichloro-BODIPY that readily undergoes regioselective Stille coupling at the 8-position, or homo/mixed couplings at the 3,8- or 3,5- and 8-positions. Stepwise and controlled replacement of the 3,5- and 8-chlorine atoms using Stille reagents results in formation of a completely unsymmetrical trisubstituted BODIPY. Several examples of unsymmetrical BODIPYs were synthesized and characterized using this methodology. Structure features of new BODIPYs are discussed within the context of 14 new X-ray structures, and photophysical parameters of all new BODIPY compounds are reported and discussed.
PMCID: PMC4227577  PMID: 25268574
4.  Impact of Substituents and Nonplanarity on Nickel and Copper Porphyrin Electrochemistry: First Observation of a CuII/CuIII Reaction in Nonaqueous Media 
Inorganic Chemistry  2014;53(19):10772-10778.
Electrochemical studies of the oxidation of dodecasubstituted and highly nonplanar nickel porphyrins in a noncoordinating solvent have previously revealed the first nickel(III) porphyrin dication. Herein, we investigate if these nonplanar porphyrins can also be used to detect the so far unobserved copper(III) porphyrin dication. Electrochemical studies of the oxidation of (DPP)Cu and (OETPP)Cu show three processes, the first two of which are macrocycle-centered to give the porphyrin dication followed by a CuII/CuIII process at more positive potential. Support for the assignment of the CuII/CuIII process comes from the linear relationships observed between E1/2 and the third ionization potential of the central metal ions for iron, cobalt, nickel, and copper complexes of (DPP)M and (OETPP)M. In addition, the oxidation behavior of additional nonplanar nickel porphyrins is investigated in a noncoordinating solvent, with nickel meso-tetraalkylporphyrins also being found to form nickel(III) porphyrin dications. Finally, examination of the nickel meso-tetraalkylporphyrins in a coordinating solvent (pyridine) reveals that the first oxidation becomes metal-centered under these conditions, as was previously noted for a range of nominally planar porphyrins.
A series of nickel(II) meso-tetraalkylporphyrins was electrochemically investigated along with nickel(II) and copper(II) derivatives of dodecaphenylporphyrin and octaethyltetraphenylporphyrin. Each investigated porphyrin exhibits three oxidations, the first two of which are macrocycle-centered to give the porphyrin dication followed by an MII/MIII process at more positive potentials.
PMCID: PMC4186666  PMID: 25253031
5.  Syntheses, properties and cellular studies of metalloisoporphyrins 
b-Bilene hydrochlorides are shown to be improved intermediates for the synthesis of metallo-isoporphyrins in enhanced yields (28% vs. 6%). Several new diamagnetic zinc(II) and a novel paramagnetic copper(II) isoporphyrin salts were also obtained using this approach. Metal-free isoporphyrins were also isolated. In vitro studies using human carcinoma HEp2 cells show that all metallo-isoporphyrins accumulate within cells and localize partially in the mitochondria. The zinc-isoporphyrins were found to be moderately phototoxic while the copper complex showed the lowest phototoxicity, maybe as a result of its paramagnetic nature.
PMCID: PMC3383767  PMID: 22745526
intracellular localization; metalloisoporphyrins; porphyrins; synthesis; toxicity
6.  Synthesis, spectroscopic, and cellular properties of α-pegylated cis-A2B2- and A3B-types ZnPcs 
Journal of porphyrins and phthalocyanines  2014;18(10-11):1021-1033.
A series of pegylated cis-A2B2- or A3B-type ZnPcs, substituted on the α-positions with tri(ethylene glycol) and hydroxyl groups, were synthesized from a new bis-phthalonitrile. A clamshell-type bis-phthalocyanine was also obtained as a byproduct. The hydroxyl group of one ZnPc was alkylated with 3-dimethylaminopropyl chloride to afford a pegylated ZnPc functionalized with an amine group. All mononuclear ZnPcs were soluble in polar organic solvents, showed intense Q absorptions in DMF, and had fluorescence quantum yields in the range 0.10–0.23. The clamshell-type bis-phthalocyanine adopts mainly open shell conformations in DMF, and closed clamshell conformations in chloroform. All ZnPcs were highly phototoxic to human carcinoma HEp2 cells, particularly the amino-ZnPc mainly protonated under physiological conditions, which showed the highest phototoxicity (IC50 = 0.5 μM at 1.5 J/cm2) and dark cytotoxicity (IC50 = 22 μM), in part due to its high cellular uptake. The ZnPcs localized in multiple organelles, including mitochondria, lysosomes, Golgi and ER.
PMCID: PMC4459643  PMID: 26064037
phthalocyanine; PEG; photosensitizer; cytotoxicity; cellular uptake
7.  Palladium(0) catalyzed 2,2′-bipyrrole syntheses 
Several 2-iodopyrroles are used in Pd(0) catalyzed homocoupling reactions at room temperature in the presence of water to efficiently synthesize 2,2′-bipyrroles. These 2,2′-bipyrroles are strongly luminous materials and have high fluorescence quantum yields.
PMCID: PMC3163486  PMID: 21886429
bipyrrole; homocoupling; iodopyrrole; palladium
8.  Synthesis and Transformations of 5-Chloro-2,2′-Dipyrrins and Their Boron Complexes, 8-Chloro-BODIPYs** 
Symmetric dipyrrylketones 1a,b were synthesized in two steps from the corresponding α-free pyrroles, by reaction with thiophosgene followed by oxidative hydrolysis under basic conditions. The dipyrrylketones produced the corresponding 5-chloro-dipyrrinium salts or 5-ethoxy-dipyrrins on reaction with phosgene or Meerwein’s salt, respectively. Boron complexation of the dipyrrins afforded the corresponding 8-functionalized BODIPYs (borondipyrromethenes) in high yields. The 5-chloro-dipyrrinium salts reacted with methoxide or ethoxide ions to produce monopyrrole esters, presumably via a 5,5-dialkoxy-dipyrromethane intermediate. In contrast, 8-chloro-BODIPYs underwent a variety of nucleophilic substitutions of the chloro group in the presence of alkoxide ions, Grignard reagents, and thiols. In the presence of excess alkoxide or Grignard reagent, at room temperature or above, substitution at the boron center also occurred. The 8-chloro-BODIPY was a particularly useful reagent for the preparation of 8-aryl-, 8-alkyl-, and 8-vinyl-substituted BODIPYs in very high yields, using Pd0-catalyzed Stille cross-coupling reactions. The X-ray structures of eleven BODIPYs and two pyrroles are presented, and the spectroscopic properties of the synthesized BODIPYs are discussed.
PMCID: PMC4012389  PMID: 24616111
bodipy; dipyrrin; dipyrrylketone; fluorescence
9.  Phenyl Derivative of Iron 5,10,15-Tritolylcorrole 
Inorganic Chemistry  2014;53(8):4215-4227.
The phenyl–iron complex of 5,10,15-tritolylcorrole was prepared by reaction of the starting chloro–iron complex with phenylmagnesium bromide in dichloromethane. The organometallic complex was fully characterized by a combination of spectroscopic methods, X-ray crystallography, and density functional theory (DFT) calculations. All of these techniques support the description of the electronic structure of this phenyl–iron derivative as a low-spin iron(IV) coordinated to a closed-shell corrolate trianion and to a phenyl monoanion. Complete assignments of the 1H and 13C NMR spectra of the phenyl–iron derivative and the starting chloro–iron complex were performed on the basis of the NMR spectra of the regioselectively β-substituted bromo derivatives and the DFT calculations.
The preparation of complex 1 fills a gap in the series of triarylcorrole iron derivatives. The spectroscopic and theoretical characterization of this complex indicates that it can be described as an Fe(IV) derivative, with a nonoxidized corrole species, acting as a trianionic ligand. However also in this case significant spin density is present on the corrole ring, as predicted by DFT calculations and confirmed by the 1H NMR isotropic shifts.
PMCID: PMC4002138  PMID: 24697623
10.  Syntheses and Functionalizations of Porphyrin Macrocycles 
Current organic synthesis  2014;11(1):3-28.
Porphyrin macrocycles have been the subject of intense study in the last century because they are widely distributed in nature, usually as metal complexes of either iron or magnesium. As such, they serve as the prosthetic groups in a wide variety of primary metabolites, such as hemoglobins, myoglobins, cytochromes, catalases, peroxidases, chlorophylls, and bacteriochlorophylls; these compounds have multiple applications in materials science, biology and medicine. This article describes current methodology for preparation of simple, symmetrical model porphyrins, as well as more complex protocols for preparation of unsymmetrically substituted porphyrin macrocycles similar to those found in nature. The basic chemical reactivity of porphyrins and metalloporphyrin is also described, including electrophilic and nucleophilic reactions, oxidations, reductions, and metal-mediated cross-coupling reactions. Using the synthetic approaches and reactivity profiles presented, eventually almost any substituted porphyrin system can be prepared for applications in a variety of areas, including in catalysis, electron transport, model biological systems and therapeutics.
PMCID: PMC4251786  PMID: 25484638
Aromaticity; porphyrin; pyrrole; reactivity; substitutions; synthesis
11.  β-Pyrazino-fused tetrarylporphyrins 
Dyes and pigments : an international journal  2013;99(1):10.1016/j.dyepig.2013.04.024.
A novel method for the preparation of β-fused porphyrin dyads was developed that exploits a one-pot reaction of 2,3-diaminoporphyrins with diethyl oxalate. This approach provides good yields of the zinc β-fused dyad and the corresponding free-base, opening the way for preparation of several metal derivatives to permit modulation of optoelectronic characteristics for commercial applications.
PMCID: PMC3863362  PMID: 24347747
β-fused-porphyrin; Dietyl oxalate; α-dione porphyrin; 2,3-Diaminoporphyrin; DSSC; Porphyrin dyad electrochemistry
12.  Differences in microbial signatures between rectal mucosal biopsies and rectal swabs 
Gut Microbes  2012;3(6):530-535.
There is growing evidence the microbiota of the large bowel may influence the risk of developing colorectal cancer as well as other diseases including type-1 diabetes, inflammatory bowel diseases and irritable bowel syndrome. Current sampling methods to obtain microbial specimens, such as feces and mucosal biopsies, are inconvenient and unappealing to patients. Obtaining samples through rectal swabs could prove to be a quicker and relatively easier method, but it is unclear if swabs are an adequate substitute. We compared bacterial diversity and composition from rectal swabs and rectal mucosal biopsies in order to examine the viability of rectal swabs as an alternative to biopsies. Paired rectal swabs and mucosal biopsy samples were collected in un-prepped participants (n = 11) and microbial diversity was characterized by Terminal Restriction Fragment Length polymorphism (T-RFLP) analysis and quantitative polymerase chain reaction (qPCR) of the 16S rRNA gene. Microbial community composition from swab samples was different from rectal mucosal biopsies (p = 0.001). Overall the bacterial diversity was higher in swab samples than in biopsies as assessed by diversity indexes such as: richness (p = 0.01), evenness (p = 0.06) and Shannon’s diversity (p = 0.04). Analysis of specific bacterial groups by qPCR showed higher copy number of Lactobacillus (p < 0.0001) and Eubacteria (p = 0.0003) in swab samples compared with biopsies. Our findings suggest that rectal swabs and rectal mucosal samples provide different views of the microbiota in the large intestine.
PMCID: PMC3495790  PMID: 23060016
colon cancer; adenomas; mucosal biopsies; rectal swabs; bacteria
13.  Copper β-trinitrocorrolates 
Journal of porphyrins and phthalocyanines  2013;17(6-7):10.1142/S1088424613500120.
The β-nitration reaction carried out on the corrole macrocycle has been shown to be extremely regioselective, although the reduced symmetry of the macrocycle could potentially lead to a huge number of possible regioisomers. We recently reported that the careful use of AgNO2/NaNO2 as a nitrating system enabled the achievement in good yields of mono- and dinitro-derivatives on both corrole free base and its copper complex, proving to be an efficient and cost-effective method. In this work, we present a detailed study of the scope of this method using TtBuCorrH3 as a model corrole. A further increase of the oxidant pushes the nitration up to the functionalization of three β-pyrrolic positions, although concomitant decomposition of the macrocycle is also observed. The application of the proven nitration method with a five-fold excess of both silver and sodium nitrites with respect to corrole, afforded the 2,3,17-(NO2)3-TtBuPCorrCu as the main product, in 25% yield, together with traces of another compound identified by X-ray crystallographic analysis as the 3,8,17-(NO2)3-TtBuPCorrCu isomer. In light of these recent results, we also reinvestigated the characterization of the nitration products obtained from bis-substitution reactions, allowing among others the identification of the copper 3,8-(NO2)2 corrolate.
PMCID: PMC3811046  PMID: 24179331
corrole; β-functionalization; nitration; AgNO2
14.  β-Nitro-5,10,15-tritolylcorroles 
Inorganic Chemistry  2012;51(12):6928-6942.
Functionalization of the β-pyrrolic positions of the corrole macrocycle with –NO2 groups is limited at present to metallocorrolates due to of the instability exhibited by corrole free bases under oxidizing conditions. A careful choice of the oxidant can limit the transformation of corroles into decomposition products or isocorrole species, preserving the corrole aromaticity, and thus allowing the insertion of nitro groups onto the corrole framework. Here we report results obtained by reacting 5,10,15-tritolylcorrole (TTCorrH3) with the AgNO2/NaNO2 system, to give mono- and di-nitrocorrole derivatives when stoichiometry is carefully controlled. Reactions were found to be regioselective, affording the 3-NO2TTCorrH3 and 3,17-(NO2)2TTCorrH3 isomers as the main products in the case of mono- and di-substitution, in 53 and 20% yields, respectively. In both cases, traces of other mono- and di-substituted isomers were detected, which were structurally characterized by X-ray crystallography. The influence of the β-nitro substituents on the corrole properties is studied in detail by UV-visible, electrochemical, and spectroelectrochemical characterization of these functionalized corroles. Density Functional Theory (DFT) and time-dependent DFT (TDDFT) calculations of the ground and excited state properties of these β-nitrocorrole derivatives also afforded significant information, closely matching the experimental observations. It is found that the β-NO2 substituents conjugate with the π-aromatic system of the macrocycle, which initiates significant changes in both the spectroscopic and redox properties of the so functionalized corroles. This effect is more pronounced when the nitro group is introduced at the 2-position, because in this case the conjugation is, for steric reasons, more efficient than in the 3-nitro isomer.
PMCID: PMC3381796  PMID: 22668242
15.  β-Nitro Derivatives of Iron Corrolates 
Inorganic Chemistry  2012;51(6):3910-3920.
Two different methods for the regioselective nitration of different meso-triarylcorroles leading to the corresponding β-substituted nitrocorrole iron complexes have been developed. A two-step procedure affords three Fe(III) nitrosyl products - the unsubstituted corrole, the 3-nitrocorrole and the 3,17-dinitrocorrole. In contrast, a one-pot synthetic approach drives the reaction almost exclusively to formation of the iron nitrosyl 3,17-dinitrocorrole. Electron-releasing substituents on the meso-aryl groups of the triarylcorroles induce higher yields and longer reaction times than what is observed for the synthesis of similar triarylcorroles with electron-withdrawing functionalities, and these results can be confidently attributed to the facile formation and stabilization of an intermediate iron corrole π-cation radical. Electron-withdrawing substituents on the meso-aryl groups of triarylcorrole also seem to labilize the axial nitrosyl group which, in the case of the pentafluorophenylcorrole derivative, results in the direct formation of a disubstituted iron μ-oxo dimer complex. The influence of meso-aryl substituents on the progress and products of the nitration reaction was investigated. In addition, to elucidate the most important factors which influence the redox reactivity of these different iron nitrosyl complexes, selected compounds were examined by cyclic voltammetry and thin-layer UV-visible or FTIR spectroelectrochemistry in CH2Cl2.
PMCID: PMC3307940  PMID: 22394192
16.  Demetalation of Silver(III) Corrolates 
Inorganic chemistry  2009;48(14):6879-6887.
Several procedures for the demetalation of silver(III) corrolates have been tested. Acidic conditions induce removal of the silver ion but they can also promote concomitant oxidation of the corrole nucleus to an isocorrole species, the degree of which will depend upon the specific acidic media. This oxidation cannot be completely avoided by addition of hydrazine, particularly in the case of 3-NO2 substituted complexes which are quantitatively converted into the corresponding 3-NO2, 5-hydroxy isocorroles upon silver ion removal. Several β-nitro isocorrole products were isolated, and one was structurally characterized. Electrochemical and chemical reductive methods for silver(III) corrolates demetalation were then tested with the aim to avoid the formation of isocorroles. While reaction with sodium borohydride was shown to be quite effective to demetalate unsubstituted silver corrolates this was not the case for the β-nitro derivatives where the peripheral nitro group is reduced by borohydride giving the corresponding 3-amino free base corrole species. For the β-nitro corrole silver complexes, a successful approach was obtained using DBU/THF solutions which afforded the 3-NO2 corrole free-base compound as a single reaction product in good yield. These conditions were also effective for unsubstituted corroles although longer reaction times were necessary in this case. To study in greater detail the corrole demetalation behavior, selected Ag(III) derivatives were characterized by cyclic voltammetry in pyridine, and the demetalation products spectrally characterized after controlled potential reduction in a thin-layer spectroelectrochemical cell.
PMCID: PMC3538369  PMID: 19548683
17.  The binding of analogs of porphyrins and chlorins with elongated side chains to albumin 
European biophysics journal : EBJ  2009;38(7):847-855.
In previous studies, we demonstrated that elongation of side chains of several sensitizers endowed them with higher affinity for artificial and natural membranes and caused their deeper localization in membranes. In the present study, we employed eight hematoporphyrin and protoporphyrin analogs and four groups containing three chlorin analogs each, all synthesized with variable numbers of methylenes in their alkyl carboxylic chains. We show that these tetrapyrroles’ affinity for bovine serum albumin (BSA) and their localization in the binding site are also modulated by chain lengths. The binding constants of the hematoporphyrins and protoporphyrins to BSA increased as the number of methylenes was increased. The binding of the chlorins depended on the substitution at the meso position opposite to the chains. The quenching of the sensitizers’ florescence by external iodide ions decreased as the side chains became longer, indicating to deeper insertion of the molecules into the BSA binding pocket. To corroborate this conclusion, we studied the efficiency of photodamage caused to tryptophan in BSA upon illumination of the bound sensitizers. The efficiency was found to depend on the side-chain lengths of the photosensitizer. We conclude that the protein site that hosts these sensitizers accommodates different analogs at positions that differ slightly from each other. These differences are manifested in the ease of access of iodide from the external aqueous phase, and in the proximity of the photosensitizers to the tryptophan. In the course of this study, we developed the kinetic equations that have to be employed when the sensitizer itself is being destroyed.
PMCID: PMC3523108  PMID: 19330323
Albumin; Binding; Chlorin; Hematoporphyrin; Protoporphyrin; Photosensitization
18.  The role of propionates in substrate binding to heme oxygenase from Neisseria meningitidis; A NMR study† 
Biochemistry  2012;51(36):7054-7063.
Heme oxygenase, HO, cleaves hemin into biliverdin, iron and CO. For mammalian HOs, both native hemin propionates are required for substrate binding and activity. The HO from the pathogenic bacterium Neisseria meningitidis, NmHO, possesses a crystallographically undetected C-terminal fragment that by solution 1H NMR is found to fold and interact with the active site. One of the substrate propionates has been proposed to form a salt bridge to the C-terminus rather than to the conventional buried cationic side chain in other HOs. Moreover, the C-terminal dipeptide Arg208His209 cleaves spontaneously over ~24 hours at a rate dependent on substituent size. 2D 1H NMR of NmHO azide complexes with hemins with selectively deleted or rearranged propionates all bind to NmHO with a structurally conserved active site as reflected in optical spectra and NMR NOESY cross peak and hyperfine shift patterns. In contrast to mammalian HOs, NmHO requires only a single propionate interacting with the buried terminus of Lys16 to exhibit full activity and tolerates the existence of a propionate at the exposed 8-position. The structure of the C-terminus is qualitatively retained upon deletion of the 7-propionate but a dramatic change in the 7-propionate carboxylate 13C chemical shift upon C-terminal cleavage confirms its role in the interaction with the C-terminus. The stronger hydrophobic contacts between pyrroles A and B with NmHO contribute more substantially to the substrate binding free energy than in mammalian HOs, “liberating” one propionate to stabilize the C-terminus. The functional implications of the C-terminus in product release are discussed.
PMCID: PMC3514545  PMID: 22913621
19.  Syntheses and Cellular Investigations of 173-, 152- and 131-Amino Acid Derivatives of Chlorin e61 
Journal of medicinal chemistry  2011;54(21):7464-7476.
A series of amino acid conjugates of chlorin e6, containing lysine or aspartic acid residues in positions 173, 152 or 131 of the macrocycle were synthesized and investigated as photosensitizers for photodynamic therapy of tumors. All three regioisomers were synthesized in good yields and in 5 steps or less from pheophytin a (1). In vitro investigations using human carcinoma HEp2 cells show that the 152-lysyl regioisomers accumulate the most within cells, and the most phototoxic are the 131 regioisomers. The main determinant of biological efficacy appears to be the conjugation site, probably because of molecular conformation. Molecular modeling investigations reveal that the 173-substituted chlorin e6 conjugates are L-shaped, the 152 and 131 regioisomers assume extended conformations, and the 131 derivatives are nearly linear. It is hypothesized that the 131-aspartylchlorin e6 conjugate may be a more efficient photosensitizer for PDT than the commercial currently used 152 derivative.
PMCID: PMC3208129  PMID: 21936519
20.  The Amination Reaction on Copper and Germanium β-Nitrocorrolates 
Inorganic chemistry  2011;50(17):8281-8292.
Copper and germanium complexes of β-substituted nitrocorroles were reacted with 4-amino-4H-1,2,4-triazole to give the corresponding β-amino-β-nitro derivatives, in moderate to good yields. This is the first successful example of a vicarious nucleophilic substitution performed on corrole derivatives, because the same reaction carried out on silver complexes afforded the corresponding 6-azahemiporphycenes by way of corrole ring expansion. The first step of this work is related to the modification of a synthetic protocol for preparation of the β-substituted nitro corroles. The nitration reaction was carried out on a copper corrole using NaNO2 as the primary source of NO2− coupled with AgNO2 used as oxidant. By variation of the molar ratio of the reagents it was possible to direct the product distribution towards mono- and di-nitro derivatives. The reaction between mono- and di-nitro derivatives of (TtBuCorrCu) with 4-amino-4H-1,2,4-triazole gave good results, leading to the isolation of 2,3-(NH2)(NO2)-TtBuCorrCu and 2,18-(NH2)2-3,17-(NO2)2-TtBuCorrCu in moderate yields. To elucidate factors that influence the reaction, and to highlight the different behavior observed for different metal complex substrates, the electrochemistry of three copper complexes, TtBuPCorrCu, (NO2)TtBuPCorrCu and (NO2)2TtBuPCorrCu, were studied by cyclic voltammetry and thin-layer UV-visible spectroelectrochemistry. The nitro groups on (NO2)xTtBuPCorrCu are highly electron-withdrawing, which leads not only to a substantial positive shift of all redox potentials, but also to a unique redox behavior and UV-vis spectrum of the singly reduced product as compared to the parent compound, TtBuPCorrCu. Finally, the amination reaction was carried out on a Ge(IV) nitrocorrolate, giving in good yield the 2-amino-3-nitroderivative, which was structurally characterized by single crystal X-ray crystallography.
PMCID: PMC3169082  PMID: 21797194
21.  Synthetic protocols for the nitration of corroles 
Journal of porphyrins and phthalocyanines  2011;15(9-10):1085-1092.
The modification of peripheral positions of corroles by introduction of nitro groups is an important functionalization of this macrocycle. The nitro substituent strongly influences the corrole behavior leading to the preparation of macrocycles with different properties, which can be of interest for their exploitation as catalysts, sensing layers in chemical sensors or in the field of supramolecular chemistry. In the last few years we have developed different routes for the β-nitration of the corrole ring, and we report here novel synthetic protocols which can allow the formation of tri- and tetranitro derivatives, as demonstrated by X-ray analysis. In all of the methodologies used, the presence of isocorrole species as reaction intermediates was established, which regenerated the corresponding corrole by metal insertion.
PMCID: PMC3266369  PMID: 22287833
corrole; nitration; isocorrole
22.  Influence of substrate modification and C-terminal truncation on the active site structure of substrate-bound heme oxygenase from Neisseriae meningitidis; A 1H NMR study† 
Biochemistry  2011;50(41):8823-8833.
Heme oxygenase, HO, from the pathogenic bacterium N. meningitidis, NmHO, which secures host iron, shares many properties with mammalian HOs, but also exhibits some key differences. The crystal structure appears more compact and the crystal-undetected C-terminus interacts with substrate in solution. The unique nature of substrate-protein, specifically pyrrole-I/II-helix-2, peripheral interactions in NmHO are probed by 2D 1H NMR to reveal unique structural features controlling substrate orientation. The thermodynamics of substrate orientational isomerism are mapped for substrates with individual vinyl → methyl → hydrogen substitutions and with enzyme C-terminal deletions. NmHO exhibits significantly stronger orientational preference, reflecting much stronger and selective pyrrole-I/II interactions with the protein matrix, than in mammalian HOs. Thus, replacing bulky vinyls with hydrogens results in a 180° rotation of substrate about the α,γ-meso axis in the active site. A "collapse" of the substrate pocket as substrate size decreases is reflected in movement of helix-2 toward the substrate as indicated by significant and selective increased NOESY cross peak intensity, increase in steric Fe-CN tilt reflected in the orientation of the major magnetic axis, and decrease in steric constraints controlling the rate of aromatic ring reorientation. The active site of NmHO appears "stressed" for native protohemin and its "collapse" upon replacing vinyls by hydrogen leads to a factor ~102 increase in substrate affinity. Interaction of the C-terminus with the active site destabilizes the crystallographic protohemin orientation by ~0.7 kcal/mol, which is consistent with optimizing the His207-Asp27 H-bond. Implications of the active site "stress" for product release are discussed.
PMCID: PMC3250371  PMID: 21870860
23.  Effect of Overall Charge and Charge Distribution on Cellular Uptake, Distribution and Phototoxicity of Cationic Porphyrins in HEp2 Cells 
Five cationic porphyrins bearing one to four -N(CH3)3+ groups linked to the p-phenyl positions of 5,10,15,20-tetraphenylporphyrin (TPP) were synthesized in order to study the effect of overall charge and its distribution on the cellular uptake, phototoxicity and intracellular localization using human carcinoma HEp2 cells. The di-cationic porphyrins DADP-o and DADP-a accumulated the most within cells and preferentially localize within vesicular compartments and in mitochondria. Of these two only DADP-a was phototoxic to the cells (IC50 = 3 µM at 1 J/cm2). The mono-cationic porphyrin MAP was found to be the most phototoxic of the series, and it localized mainly in lipid membranes, including the plasma membrane, ER, mitochondria, and Golgi. Both the tri-cationic porphyrin TRAP and the tetra-cationic porphyrin TEAP localized subcellularly mainly in the mitochondria, but of the two only TEAP showed moderate phototoxicity (IC50 = ~8 µM at 1 J/cm2). Our results suggest that MAP is the most promising PDT photosensitizer, and that both DADP-o and TRAP might find application as transport vehicles for therapeutics into cells.
PMCID: PMC3161426  PMID: 20558079
cationic porphyrin; PDT; cytotoxicity; cellular uptake; subcellular localization
24.  Efficient synthesis and reactions of 1,2-dipyrrolylethynes 
Various dipyrroles possess important motifs for construction of pyrrole-containing pigments. A series of 1,2-dipyrrolylethynes (4a–d) has been efficiently synthesized using an improved one-pot double Sonagashira coupling from trimethylsilylethyne and various 2-iodopyrroles. The resulting 1,2-dipyrrolylethynes were further transformed into novel indolyl-, ethenyl- and carboranyl-dipyrroles (5–7) using the Larock indole synthesis, stereoselective catalytic hydrogenation, or B10H14. Indolyl-dipyrroles were found to selectively bind fluoride ions using one pyrrolic and the indolyl NHs, whereas the carboranyl- and ethenyl-dipyrroles are potentially valuable precursors for the synthesis of porphyrin isomers and expanded pigments.
PMCID: PMC3150752  PMID: 21822371
carborane; dipyrrole; indole; Larock; Sonagashira
25.  Synthesis and Characterization of Free-Base, Copper and Nickel Isocorroles 
Inorganic chemistry  2010;49(12):5766-5774.
A series of free-base and metalated isocorroles represented as (TT-n-iso-Cor)H2 and (TT-n-iso-Cor)MII, where n = 5 or 10 and M = Ni or Cu, were synthesized and characterized by electrochemistry and spectroelectrochemistry in CH2Cl2 containing 0.1 M TBAP. A metalation of the free-base macrocycles with CoII, MnIII or ZnII was also attempted but was unsuccessful. Five isocorroles were isolated and shown to undergo two stepwise oxidations to give π-cation radicals and dications in CH2Cl2, with the most stable products being obtained in the case of the 10-substituted derivatives. The same isocorroles could also be reduced by one or two electrons but the initial one-electron addition products are unstable and undergo a rapid chemical reaction giving a reduced corrole or corrole-like product, which could be reoxidized to the corresponding (TTCor)M at a controlled positive potential. This series of reactions effectively gives an isocorrole to corrole conversion upon reduction and reoxidation and was monitored by both electrochemistry and thin-layer spectroelectrochemistry.
PMCID: PMC2912170  PMID: 20499899

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