Site-specific recognition of guanosine by manganese(III) corroles in DNA non-duplex regions through active oxygen transfer

DNA damage plays an important role in cellular processes. Besides natural protein nucleases, different types of efficient agents for DNA damage have been developed over recent decades in the search for new anticancer and antiviral drugs. In addition to the double-stranded configuration, DNA structures also include some non-duplex regions, which are considered to be from spontaneous errors in DNA replication, thus playing an important role for cells. Herein, we focused on these non-duplex regions of DNA and generated manganese(III) corroles, which exhibit a highly selective cleavage ability for guanosine units located at non-duplex portions, such as loops and bulges. The cleavage mechanism was demonstrated to be a manganese-induced oxidation process. The results given herein show a molecular approach that could specifically probe the guanosine units in DNA non-duplex structures, thus representing a promising step in the construction of tools to target non-duplex structures in chromosomes.     

New and efficient arrays for photoinduced charge separation based on perylene bisimide and corroles

The bichromophoric systems C2-PI, C3-PI, and C3-PPI consisting of corrole and perylene bisimide units and representing one of the rare cases of elaborate structures based on corrole, have been synthesized. Corroles C2 and C3 are, respectively, meso-substituted corroles with 2,6-dichlorophenyl and pentafluorophenyl substituents at the 5 and 15 positions. The three dyads were prepared by divergent strategy with the corrole-forming reaction as the last step of the sequence. C2-PI and C3-PI differ in the nature of the corroles, whereas C3-PI differs from C3-PPI in the presence of a further phenyl unit in the linker between photoactive units. The dyads display spectroscopic properties which are the superposition of the component spectra, indicating a very weak electronic coupling. Excitation of the corrole unit leads to charge separation with a rate which decreases from 2.4 x 10(10), to 5.0 x 10(9), and to 4.9 x 10(7) s(-1) for C2-PI, C3-PI, and C3-PPI, respectively, where the reaction is characterized by a delta G degrees >0. Excitation of the perylene bisimide unit is followed by competing reactions of: 1) energy transfer to the corrole unit, which subsequently deactivates to the charge-separated state and; 2) electron transfer to directly form the charge-separated state. The ratio of electron-to-energy-transfer rates is 9:1 and 1:1 for C3-PI and C3-PPI, respectively. The yield of charge separation is essentially 100 % for C2-PI and C3-PI, and approximately 50 % (excitation of peryleneimide) or 15 % (excitation of the corrole) for C3-PPI. The lifetime of the charge-separated state, observed for the first time in corrole-based structures, is 540 ps for C2-PI, 2.5 ns for C3-PI, and 24 ns for C3-PPI, respectively. This is in agreement with an inverted behavior, according to Marcus theory.     

Iron(III) corroles and porphyrins as superior catalysts for the reactions of diazoacetates with nitrogen- or sulfur-containing nucleophilic substrates: synthetic uses and mechanistic insights

A thorough mechanistic investigation has been performed on the reactions of primary and secondary amines with diazoacetates, which proceed uniquely quickly and efficiently when catalyzed by iron(III) corroles and porphyrins. Two major differences in relation to other metal-based catalysts are that the iron complexes are not poisoned by excess amine and that metal-carbene intermediates are apparently not involved in the reaction pathway. The results instead point towards nitrogen ylide intermediates formed by nucleophilic attack of the amines on diazoacetate-coordinated iron complexes. Nitrogen ylides are also formed when allyl- and propargyl-substituted tertiary amines react with diazoacetates, a scenario that smoothly leads to 2,3-rearrangement reaction products with catalytic amounts of the iron(III) complexes. Similar findings regarding the superiority of the iron(III) complexes (in terms of catalyst loading, chemical yields, and reaction conditions) were obtained with thiols (S--H insertion) and sulfides (2,3-rearrangement reactions), which suggest similar mechanisms operate in these cases.     

meso-meso-Linked corrole dimers with modified cores: synthesis, characterization, and properties

The synthesis and characterization of the first examples of core-modified corrole dimers linked through the meso positions are described. The dimers are obtained by a simple Ag(I)- or Fe(III)-catalyzed coupling reaction in near-quantitative yields. The corroles obtained are metalated with metal ions, such as Cu(II) and Ni(II). The electronic-absorption spectral studies reveal weak electronic interaction between the two subunits and the exciton coupling observed for the free-base corrole dimer (1717 cm(-1)) is lower than that for the corresponding protonated derivative (4081 cm(-1)). The solution-state structure derived from (1)H and two-dimensional NMR spectral studies reveals a noncoplanar arrangement of two corrole units. Geometry optimization at the B3LYP-631G level also confirms the noncoplanar arrangement of corroles with a dihedral angle of 64.8 degrees between two corrole planes. The electron paramagnetic resonance (EPR) and magnetic characterization studies on the paramagnetic copper-metalated dimer indicate that both copper ions behave as independent spins without any noticeable interaction. Results of fluorescence studies reveal a bathochromic shift of about 60 nm upon dimerization. The first hyperpolarizability (beta) measured by using the hyper Rayleigh scattering (HRS) method reveals doubling of the beta values on progressing from monomer to dimer, attributed to enhanced pi conjugation. The use of copper dimers in the photocleavage of DNA is also explored. It is shown that the bimetallic copper dimer selectively cleaves the nucleic acids without affecting the proteins, suggesting a possible application of the copper complex in the removal of nucleic acid contaminants from protein extracts through a simple photolytic pathway.     

Modified expanded corrole-ferrocene conjugates: syntheses, structure and properties

Syntheses, characterization and properties of expanded corrole-ferrocene conjugates are reported. Ferrocenyl group are covalently linked to the corrole macrocycle through three different spacers groups. The synthetic strategy involved prior insertion of ferrocene with spacers to the dipyrromethane unit followed by a "3+2" acid-catalyzed oxidative coupling methodology. The optical and emission data of the expanded corrole-ferrocene conjugates depend on the nature and length of the spacer groups and the maximum effects are seen where ferrocene is directly linked to the meso carbon of macrocycle. The single crystal X-ray structure of two expanded corrole-ferrocene conjugates; [22]pentaphyrin (1.1.0.1.0) with different meso substituents, clearly reveal shortening of the C-C bond length linking the meso carbon and the aryl substituent containing the ferrocene moiety relative to meso aryl substituents without ferrocene. The results suggest that an electronic interaction between the two pi systems. Electrochemical data reveal harder oxidation for the ferrocene unit in the conjugates relative to free ferrocene; this suggests the electron donating nature of the ferrocene. The first corrole ring oxidation shows easier oxidation relative to 1 and the magnitude of shifts in potential is inversely proportional to the length of spacer. The molecular first hyperpolarizabilities (beta) measured at 1064 nm by HRS method vary in the range 20-32x10(-30) esu and imply that the beta values can be increased by enhancing the number of mobile electrons in the conjugation. The conjugates form 1:1 metal complex with the Rh(I) where rhodium is coordinated to one amino and one imino nitrogen of the dipyrromethane unit.     

Selective covalent binding of a positively charged water-soluble benzoheterocycle triosmium cluster to single- and double-stranded DNA

The water-soluble triosmium cluster [Os₃(CO)₉(μ-η²-(4-CHO)C₉H₅N)(μ-H)(P(OCH₂CH₂N(CH₃)₃I)₃)] (4) was tested for its reactivity with plasmid DNA. In contrast to the band retardation previously observed with a related series of positively charged clusters, an intensification and retardation of three discrete bands was observed with increasing cluster concentration. In order to further investigate the apparent modification of DNA by 4, its interaction with a 22-oligomer (sequence 5′-AGT TGT GGT GAC TTT CCC AGG C-3′) was examined. Incubation with this oligonucleotide (pH 7.4 in Tris-HCl buffer and 100 mM NaCl) followed by HPLC analysis revealed the formation of three dose dependent products assigned as covalent modifications at three sites of the oligonucleotide. Incubation of 4 with ³²P-ATP labeled oligonucleotide at the 5′-end followed by treatment with piperidine and comparison with the standard Maxam-Gilbert sequencing protocol products revealed only general background cleavage, indicating that the modification products are piperidine labile and suggesting that the modification involved formation of a Schiff base. An alternative approach was then pursued which involved annealing the 4-oligonucleotide products with their complementary strand and treatment of the resulting duplex DNAwith the exonuclease, Exo III. This assay indicated three exonuclease stops, consistent with the three products observed by HPLC whose electrophoretic mobility approximately matched guanine containing fragments when compared with the Maxam-Gilbert sequencing lanes. Reduction of the 4-oligonucleotide products with borohydride reducing agents, followed by treatment with piperidine, resulted in the formation of one product (by HPLC) with the same electrophoretic mobility as the AGTT fragment based on comparison with the Maxam-Gilbert sequencing lanes. This product most likely results from reduction of an initially formed Schiff base adduct (to the corresponding amine) with the guanine of the TGT fragment of the oligonucleotide, and corresponds to the most stable of the three Schiff base adducts detected by HPLC and by incubation with the exonuclease. The other two products are less stable and competitive reduction of the free aldehyde functionality on the cluster in equilibrium with these adducts precludes their detection after treatment with the reducing agents. The formation of the Schiff base adduct is further corroborated by the model reaction of [Os₃(CO)₁₀(μ-η²-(4-CHO)C₉H₅N)(μ-H)] (4′) with acetylated guanine in nonaqueous solvents where disappearance of the aldehyde resonance and the appearance of several new resonances in the 6-9 ppm region of the ¹H NMR of the reaction mixture is noted.     

Synthesis,structure, DNA binding studies and nuclease activities of two luminescent neodymium complexes

Two neodymium(III) complexes, [Nd(Phen)(NO₃)₃(DMF)₂] (1) and [Nd(Phen)₂(NO₃)₃] (2) (phen = 1,10-phenanthroline; DMF = dimethylformamide), have been synthesized with a view to design artificial luminescent nucleases and nuclease mimics. The complexes were characterized by spectroscopic, powder, and single crystal XRD studies. The complexes, as expected, have luminescent properties. The DNA binding studies of both complexes have been carried out by spectroscopic studies e.g. electronic absorption (UV–Vis), fluorescence emission as well as viscosity measurements. The nuclease activity of the complexes has been established by gel electrophoresis using pUC19 circular plasmid DNA. The results of DNA binding as well as DNA cleavage activity and the model studies of interaction with pNPP indicate that both neodymium complexes demonstrate nuclease activity through phosphoester bond cleavage.     

Primary and secondary phosphane complexes of metalloporphyrins: isolation, spectroscopy, and X-ray crystal structures of ruthenium and osmium porphyrins binding phenyl- or diphenylphosphane

[Ru(II)(por)(PH(n)Ph(3-n))2], [Os(II)(por)(CO)(PH(n)Ph(3-n))] (n=1, 2), and [Os(II)(F20-tpp){P(OH)Ph2}(PHPh2)] (F20-tpp=5,10,15,20-tetrakis(pentafluorophenyl)porphyrinato dianion) were prepared from the reaction of [M(II)(por)(CO)] (M=Ru, Os) or [Os(VI)(por)O2] with the respective primary/secondary phosphane and characterized by 1H NMR, 31P NMR, UV/Vis, and IR spectroscopy, mass spectrometry, and elemental analysis. The reaction of [Os(VI)(por)O2] with PHPh2 also gave minor amounts of [Os(II)(por){P(OH)Ph2}2]. [Ru(II)(F20-tpp)(PH2Ph)2] exhibits a remarkable stability toward air and shows a reversible metal-centered oxidation couple at E(1/2)=0.39 V versus [Cp2Fe](+/0) in the cyclic voltammogram. The structures of [Ru(II)(F20-tpp)(PH2Ph)2] x 2CH2Cl2, [Ru(II)(4-Cl-tpp)(PHPh2)2] x 2CH2Cl2 (4-Cl-tpp=5,10,15,20-tetrakis(p-chlorophenyl)porphyrinato dianion), [Ru(II)(F20-tpp)(PHPh2)2], and [Os(II)(F20-tpp){P(OH)Ph2}2] were determined by X-ray crystallography and feature Ru-P distances of 2.3397(11)-2.3609(9) A and an Os-P distance of 2.369(2) A.     

Fine tuning of photophysical properties of meso-meso-linked ZnII-diporphyrins by dihedral angle control

A series of meso-meso-linked diporphyrins S(n) strapped with a dioxymethylene group of various length were synthesized by intramolecular Ag(I)-promoted coupling of dioxymethylene-bridged diporphyrins B(n), for n=10, 8, 6, 5, 4, 3, 2, and 1. Shortening of the strap length causes a gradual decrease in the dihedral angle between the porphyrins and increasing distortion of porphyrin ring, as suggested by MM2 calculations and (1)H NMR studies. This trend has been also suggested by X-ray crystallographic studies on the corresponding Cu(II) complexes of nonstrapped diporphyrin 2 Cu, and strapped diporphyrins S(8)Cu, S(4)Cu, and S(2)Cu. The absorption spectrum of relatively unconstrained diporphyrins S(10) strapped with a long chain exhibits split Soret bands at 414 and 447 nm and weak Q(0,0)- and prominent Q(1,0)-bands, both of which are similar to those of nonstrapped diporphyrin 2. Shortening of the strap length causes systematic changes in the absorption spectra, in which the intensities of the split Soret bands decrease, the absorption bands at about 400 nm and > 460 nm increase in intensity, and a prominent one-band feature of a Q-band is changed to a distinct two-band feature with concurrent progressive red-shifts of the lowest Q(0,0)-band. The fluorescence spectra also exhibit systematic changes, roughly reflecting the changes of the absorption spectra. The strapped diporphyrins S(n) are all chiral and have been separated into enantiomers over a chiral column. The CD spectra of the optically active S(n) display two Cotton effects at 430-450 and at about 400 nm with the opposite signs. The latter effect can be explained in terms of oblique arrangement of m( perpendicular 1) and m( perpendicular 2) dipole moments, while the former effect cannot be accounted for within a framework of the excition coupling theory. The resonance Raman (RR) spectra taken for excitation at 457.9 nm are variable among S(n), while the RR spectra taken for excitation at 488.0 nm are constant throughout the S(n) series. These photophysical properties can be explained in terms of INDO/S-SCI calculations, which have revealed charge transfer (CT) transitions accidentally located close in energy to the excitonic Soret transitions. This feature arises from a close proximity of the two porphyrins in meso-meso-linked diporphyrins. In addition to the gradual red-shift of the exciton split Soret band, the calculations predict that the high-energy absorption band at about 400 nm, the lower energy Cotton effect, and the RR spectra taken for excitation at 457.9 nm are due to the CT states which are intensified upon a decrease in the dihedral angle.     

Structure formation and catalytic activity of DNA dissolved in organic solvents

Equal-opportunity dissolver: By attaching polyethylene glycol at its 5' end, DNA (PEG-DNA) can be solubilized in various organic solvents and was shown to form G-quadruplexes by CD spectroscopy. A complex containing iron(III) protoporphyrin?IX (hemin) and G-quadruplex-forming PEG-DNA catalyzed an oxidative reaction in methanol (see scheme).     

Vilsmeier formylation of 5,10,15-triphenylcorrole: expected and unusual products

5,10,15-Triphenylcorrole (1) reacts with the Vilsmeier reagent (POCl(3)/DMF) to give the corresponding 3-formyl derivative 3 as the major product. The regioselectivity of the reaction was proven by X-ray crystallography and only traces of the 2-formyl isomer were observed. A more polar product is also observed and this compound becomes the major product when an excess of DMF is used for the preparation of the Vilsmeier reagent, while the formation of the 3-formyl isomer is almost completely suppressed. X-ray crystallography allowed us to identify this compound as the fully substituted N-ethane bridged derivative 4, formed from the attack of the Vilsmeier reagent at the inner core of the macrocycle. This compound is unique among porphyrinoid macrocycles, and further confirms the peculiarity of corrole chemistry.     

Palladium Complexes of Corroles and Sapphyrins

Palladium complexes of corrole and sapphyrin were prepared in high yield and fully characterized. The corrole provides a tetradentate/trianionic square planar coordination sphere for Pd^II, charge balanced by pyridinium. Both one and two Pd^II ions may be accommodated by the pentapyrrolic skeleton of the sapphyrin, and in each case the macrocycle acts as bidentate/monoanionic ligand and the inner-sphere square planar geometry is completed by allyl anions coordinated in an η³ fashion. NMR spectroscopy and X-ray crystallography data analyses uncovered the presence of interesting stereoisomers due to the flexibility of the ally ligands and also the pyrrole ring(s) that is/are not involved in metal binding.     

Reactivity of silole within a core-modified porphyrin environment: synthesis of 21-silaphlorin and its conversion to carbacorrole

Condensation of 1,1-dimethyl-3,4-diphenyl-2,5-bis(p-tolylhydroxymethyl)silole with pyrrole and p-tolylaldehyde did not form the expected 21,21-dimethyl-2,3-diphenyl-5,10,15,20-tetra(p-tolyl)-21-silaporphyrin, but rather its reduced derivative, 21-silaphlorin, which contains a tetrahedrally hybridised C5 carbon atom. Attempts to trap 21-silaporphyrin resulted in the serendipitous discovery of a unique transformation of 21-silaphlorin into a non-aromatic isomer of 2,3-diphenyl-5,10,15,21-tetra(p-tolyl)-carbacorrole (iso-carbacorrole). This novel carbaporphyrinoid contains a cyclopentadiene ring embedded in a tripyrrolic framework. This transformation of 21-silaphlorin to iso-carbacorrole, carried out under oxidative conditions, involves extrusion of dimethylsilylene accompanied by migration of the C(meso)-(p-tolyl) unit to create a cyclopentadiene ring directly linked to the adjacent pyrrole through a tetrahedral carbon atom. Insertion of silver or copper ions into iso-carbacorrole gave two structurally related organometallic complexes of "true" carbacorrole in which the metal(III) ions are bound by three pyrrolic nitrogen atoms and a tetrahedrally hybridised C21 atom of the cyclopentadiene moiety. In the presence of oxygen, the silver(III) carbacorrole undergoes internal oxidation to 21-oxacorrole. The structure of silver(III) carbacorrole was determined by X-ray crystallography. The C21 atom was found to have a tetrahedral geometry. The Ag-C(sp(3)) (2.046(5) A) bond length is similar to that in silver(III) carbaporphyrinoids in which a trigonal carbon atom coordinates to the metal ion. Density functional theory was applied to model the molecular and electronic structure of 21-silaphlorin and feasible isomers of carbacorrole. The total energies (kcal mol(-1) vs. iso-carbacorrole), calculated at the B3LYP/6-31G(**)//B3LYP/6-31G(*) level for carbacorrole, iso-carbacorrole, vacataporphyrin and cyclobutadienephlorin, demonstrate the energetic preference for iso-carbacorrole.