Analyses of sizable ZFS and magnetic tensors of high spin metallocomplexes.

The fictitious spin-1/2 Hamiltonian approach is the putative method to analyze the fine-structure/hyperfine ESR spectra of high spin metallocomplexes having sizable zerofield splitting (ZFS), thus giving salient principal g-values far from around g = 2 without explicitly providing their ZFS parameters in most cases. Indeed, the significant departure of the g-values from g = 2 is indicative of the occurrence of their high spin states, but naturally they never agree with true g-values acquired by quantum chemical calculations such as sophisticated DFT or ab initio MO calculations. In this work, we propose facile approaches to determine the magnetic tensors of high spin metallocomplexes having sizable ZFS, instead of performing advanced high-field/high-frequency ESR spectroscopy. We have revisited analytical expressions for the relationship between effective g-values and true principal g-values for high spins. The useful analytical formulas for the geff-gtrue relationships are given for S's up to 7/2. The genuine Zeeman perturbation formalism gives the exact solutions for S = 3/2, and for higher S's it is much more accurate than the pseudo-Zeeman perturbation approach documented so far (A. Abragam and B. Bleaney, Electron Paramagnetic Resonance of Transition Metal Ions, 1970; J. R. Pilbrow, J. Magn. Reson., 1978, 31, 479; F. Trandafir et al., Appl. Magn. Reson., 2007, 31, 553; M. Fittipaldi et al., J. Phys. Chem. B, 2008, 112, 3859), in which the E(Sx2 - Sy2) term is putatively treated to the second order. To show the usefulness of the present approach, we exploit FeIII(Cl)OEP (S = 5/2) (OEP: 2,3,7,8,12,13,17,18-octaethylporphyrin) and CoIIOEP (S = 3/2) well magnetically diluted in the diamagnetic host crystal lattice of NiIIOEP. The advantage of single-crystal ESR spectroscopy lies in the fact that the molecular information on the principal axes of the magnetic tensors is crucial in comparing with reliable theoretical results. In high spin states of metallocomplexes with sizable ZFS in pseudo-octahedral symmetry, their fine-structure ESR transitions for the principal z-axis orientation appear in the lower field far from g = 2 at the X-band, disagreeing with the putative intuitive picture obtained using relevant ESR spectroscopy. A ReIII,IV dinuclear complex in a mixed valence state exemplifies the cases, whose fine-structure/hyperfine ESR spectra of the neat crystals have been analyzed in their principal-axis system. The DFT-based/ab initio MO calculations of the magnetic tensors for all the high spin entities in this work were carried out.

Diastereoselective generation of triple-stranded helicates induced by gem-dimethyl groups on a linker.

The diastereoselectivity of the self-assembly of bis(dipyrromethene) ligands with trivalent metals was improved by introducing gem-dimethyl groups to the linker.

Self-assembly of [2×2] grids and a hexagon using bis(dipyrrin)s.

Neutral Zn(II) [2×2] grids (M(4)L(4)) and a hexagon structure (M(6)L(6)) were, for the first time, synthesized using bis(dipyrrin)s and confirmed by X-ray diffraction analysis. The channel structures in the solid state result from several intermolecular noncovalent interactions.

Synthesis of triple-stranded complexes using bis(dipyrromethene) ligands.

The reaction of an α-free, ß,ß'-linked bis(dipyrromethene) ligand with Fe(3+) or Co(3+) led to noninterconvertible triple-stranded helicates and mesocates. In the present context, a stable α-free ligand 2 has been developed and complexation of ligands 1 and 2 with diamagnetic Co(3+), Ga(3+), and In(3+) has been studied. The triple-stranded M(2)1(3) (M = Ga, In) and M(2)2(3) (M = Co, Ga, In) complexes were characterized using matrix-assisted laser desorption ionization time-of-flight spectrometry, (1)H NMR and UV-vis spectroscopy, and X-ray crystallography. Again, the (1)H NMR analysis showed that both the triple-stranded helicates and mesocates were generated in this metal-directed assembly. Consistent with our previous finding on coordinatively inert Co(3+) complexes, variable-temperature NMR spectroscopy indicated that the triple-stranded helicate and mesocate of labile In(3+) did not interconvert in solution, either. However, the diastereoselectivity of the M(2)2(3) complexes was found to improve with an increase in the reaction temperature. Taken together, this study complements the coordination chemistry of poly(dipyrromethene) ligands and provides further insight into the formation of helicates versus mesocates.

A triple-stranded helicate and mesocate from the same metal and ligand.

A pair of triple-stranded helicates and mesocates were, for the first time, isolated from the same reaction of a novel alpha-free bis(dipyrromethene) ligand with either Co(3+) or Fe(3+).

Scaffold-based design and synthesis of potent N-type calcium channel blockers.

The therapeutic agents flunarizine and lomerizine exhibit inhibitory activities against a variety of ion channels and neurotransmitter receptors. We have optimized their scaffolds to obtain more selective N-type calcium channel blockers. During this optimization, we discovered NP118809 and NP078585, two potent N-type calcium channel blockers which have good selectivity over L-type calcium channels. Upon intraperitoneal administration both compounds exhibit analgesic activity in a rodent model of inflammatory pain. NP118809 further exhibits a number of favorable preclinical characteristics as they relate to overall pharmacokinetics and minimal off-target activity including the hERG potassium channel.

Near-Infrared absorbing azo dyes: synthesis and x-ray crystallographic and spectral characterization of monoazopyrroles, bisazopyrroles, and a boron-azopyrrole complex.

Symmetric 2,5-bisazopyrroles 2(a-d) were synthesized by a one-step reaction of substituted phenyl diazonium salts [R'(Ph)N2(+)Cl-] [a, R' = 4-N(CH3)2; b, R' = 2-OH; c, R' = 2-CO2H; d, R' = 4-NO2] with pyrrole under basic conditions. Asymmetric 2,5-bisazopyrroles 3(a-d) were synthesized by reacting substituted phenyl diazonium salts [R''(Ph)N2(+)Cl-] (a, R'' = 4-OCH(3); b, R'' = H; c, R'' = 4-Br; d, R'' = 4-NO2) with 2-(4-dimethylaminophenylazo)-1H-pyrrole (1a) under the same conditions. The reactions of 2a with boron trifluoride and iodomethane provided a BF2-azopyrrole complex of 1H-pyrrolo[2,1-c]-1,2,4,5-boratriazole (4) and 2,5-bisazo-1-methylpyrrole 5. X-ray crystallographic and spectral analysis of 1a, 2a, 2b, and 4 showed that 1a has three crystal forms: 1a(I), 1a(II), and 1a(III), the latter two bearing a bicyclic ring system formed via intermolecular hydrogen bonding. Complex 4 was found to be the most planar due to a rigid trans-azo configuration and has the longest N horizontal lineN bond distances (1.322 and 1.300 Angstrom) and wavelength of maximum absorption (754 nm). The N horizontal lineN bond distances increase in the sequence of monoazopyrrole [1a(I): 1.253 Angstrom], bisazopyrrole (2a: 1.283 Angstrom), bisazopyrrole with intramolecular hydrogen bonding (2b: 1.293 and 1.293 Angstrom), and the BF2-azopyrrole complex. Their maximum absorptions shift bathochromically in the sequence of monoazopyrrole (1a: 443 nm), bisazopyrroles [2(a-d), 3(a-d), 5: 486-615 nm], and the BF2-azopyrrole complex. These results are important for the design of near-infrared absorbing azo dyes and suggest an efficient path for the preparation of near-infrared absorbing azo dyes by effectively enhancing pi-electron delocalization.

Self-assembly of oligomeric linear dipyrromethene metal complexes.

BF(2) capped dipyrrin dimers were synthesized and have been used to terminate oligomerization to form a series of controlled length oligomers; the crystal structures of the metal complexes were investigated and correlations between the structures and optical properties were established.

Facile synthesis of dicyanovinyl-di(meso-aryl)dipyrromethenes via a dipyrromethene-DDQ adduct.

The dicyano-substituted vinyl dipyrromethene and compound are near-planar and were prepared from a simple meso-aryl dipyrromethane via the DDQ adduct ; the unique structures of , and were confirmed by X-ray diffraction analysis.

Oxidized forms of a tripyrrane: alpha-tripyrrinone, beta-tripyrrinone and a C2 symmetric hexapyrrole.

alpha- and beta-tripyrrinone isomers (), and a C(2) symmetric hexapyrrole () were isolated from the oxidation of meso-perfluorophenyl tripyrrane (and meso-2,6-dichlorophenyl tripyrrane ) with DDQ under aerobic conditions, and the structure of was determined by X-ray crystallographic analysis.

Facile synthesis of unsubstituted beta,beta'-linked diformyldipyrromethanes.

Unsubstituted beta,beta'-linked diformyldipyrromethanes are promising precursors for the synthesis of novel poly dipyrromethene ligands and N-confused porphyrins. A strategy has been developed to selectively synthesize unsubstituted beta,beta'-linked diformyldipyrromethanes in moderate yields starting from 2-formylpyrrole.

Cross-metathesis of the vinyl group on tetrapyrrolic macrocycles: reactivity, selectivity, and mechanism.

To find a general strategy for modifying the peripheral structure of vinylchlorin and porphyrin substrates, cross-metathesis on the vinyl group of these tetrapyrrolic macrocycles was investigated. The N-heterocyclic carbene-containing ruthenium complex 3 efficiently catalyzed the cross-metathesis (CM) of vinylchlorins and vinylporphyrins with a variety of olefins in high E-stereoselectivity. Different substituents on the olefin dramatically influenced the reaction. While the chlorins were more reactive than the porphyrins (as free bases), the corresponding zinc complexes showed higher activity. The reaction mechanism was investigated, and an empirical model for selective CM was applied to our studies to direct further reactions.

Structure, formation and catalytic studies of a meso-palladioporphyrin intermediate in a Heck reaction.

A meso-palladioporphyrin intermediate was isolated from a Heck reaction between an iodoporphyrin and a non-activated olefin using a Pd(PPh3)2Cl2/Et3N system; its structure was characterized by NMR, MS and X-ray crystallography. Studies on its formation indicate that the Pd(II) catalyst was reduced in situ by Et3N with the assistance of water. The catalytic activity of the intermediate was confirmed by stoichiometric and catalytic reactions using a more reactive olefin, ethyl acrylate.

Site-specific prodrug release using visible light.

Using a photosensitization-singlet oxygenation-dioxetane cleavage strategy, a photodynamic prodrug system has been developed, whereby drugs bearing carbonyl groups can first be attached to a photosensitizer to give a photosensitizer-drug complex and then released from the complex upon visible light irradiation. Visible light, which has good penetration through tissue, generates singlet oxygen via the photosensitizer, which then releases the prodrug when and where required. With this system, drug mimics and methyl esters of NSAIDs have been successfully incorporated with photosensitizers related to verteporfin and then released by visible light illumination in high to quantitative yields within minutes.

Cellular and antitumor activity of a new diethylene glycol benzoporphyrin derivative (lemuteporfin).

A newly synthesized diethylene glycol functionalized chlorin-type photosensitizer, lemuteporfin, was characterized for use in photodynamic therapy (PDT) in a panel of in vitro and in vivo test systems. The photosensitizer was highly potent, killing cells at low nanomolar concentrations upon exposure to activating light. The cellular uptake of lemuteporfin was rapid, with maximum levels reached within 20 min. Mitogen-activated lymphoid cells accumulated more of the lemuteporfin than their quiescent equivalents, supporting selectivity. Photosensitizer fluorescence in the skin increased rapidly within the first few minutes following intravenous administration to mice, then decreased over the next 24 h. Skin photosensitivity reactions indicated rapid clearance of the photosensitizer. Intravenous doses as low as 1.4 micromol/kg combined with exposure to 50 J/cm2 red light suppressed tumor growth in a mouse model. In conclusion, this new benzoporphyrin was found to be an effective photosensitizer, showing rapid uptake and clearance both in vitro and in vivo. This rapid photosensitization of tumors could be useful in therapies requiring a potent, rapidly accumulating photosensitizer, while minimizing the potential for skin photosensitivity reactions to sunlight following treatment.

Separation of porphyrin-based photosensitizer isomers by laser-induced fluorescence capillary electrophoresis.

Methods for the separation of photosensitizer isomers, such as benzoporphyrin derivative monoacid, benzoporphyrin ethyl monoacid, 2-[1-hexyloxyethyl]-2-devinylpyropheophorbide-a, diethyleneglycol diester benzoporphyrin derivative, tin ethyl etiopurpurin, and phthalocyanine tetrasulfonate, have been systematically developed by CE. Detection was accomplished by UV absorption at 214 nm or by LIF with excitation at 442/488 nm and emission at 690 nm. The effects of three major experimental parameters of buffer types, organic solvents, and surfactant additives are described. The optimized separation conditions were determined so as to provide satisfactory separation efficiency and analysis time. The methods are shown to be suitable for the separation and determination of porphyrin and phthalocyanines regioisomers, diastereoisomers, and enantiomers.

Cross-metathesis reactions of vinyl-chlorins and -porphyrins catalyzed by a "second generation" Grubbs' catalyst.

The first application of olefin cross-metathesis with vinylchlorins and vinylporphyrins using a "second generation" Grubbs' catalyst is reported. Cross-metathesis products were obtained in good yields with high E-stereoselectivity.

Ni(III) complex of an N-confused porphyrin inner C-oxide.

A novel, structurally characterized Ni(III) complex of an N-confused porphyrin inner C-oxide has been synthesized from the oxidation of a Ni(II) N-confused porphyrin using OsO4. Crystal data: C53H40N5NiO.CH2Cl2, monoclinic, space group P2/a (No. 13), a=21.229(1) A, b=8.6451(5) A, c=25.762(2) A, beta=93.004(3) degrees, V=4721.6(5) A3, and Z=4.

Correlation of photosensitizer delivery to lipoproteins and efficacy in tumor and arthritis mouse models; comparison of lipid-based and Pluronic P123 formulations.

PURPOSE: The purpose of this study was the use of animal models to demonstrate the importance of drug delivery (verteporfin) to plasma lipoproteins in order to attain efficacy of photodynamic therapy (PDT) in vivo. METHODS: Photosensitizers appropriately formulated in various vehicles such as pluronics and lipid-based systems were compared to delivery of the drug in DMSO in two in vivo systems. The first was a tumor model using male DBA/2 mice inoculated intradermally with M1 rhabdomyosarcoma cells and in the second, arthritis in the MRL -lpr mouse strain was enhanced by two intradermal injections of complete Freunds adjunct. RESULTS: Those formulations in which the drug was in a monomeric form were better able to transfer drug to lipoproteins, which in turn led to superior PDT in vivo. CONCLUSIONS: The ability to introduce drug in monomeric form into the circulation correlates well with efficacy of photosensitizer formulations in mouse arthritis and tumor models.