PHOTOCHEMICAL PROPERTIES OF PORPHYRIN c: AN AGENT FOR USE IN TUMOR PHOTOTHERAPY

Abstract— The absorption and fluorescence properties of porphyrin c (P c ), the porphyrin chromophore present in cytochrome c , have been determined in several solvents and micellar environments. In aqueous buffer solutions at pH 7.5 Pc may exist in both a fluorescent monomeric form with quantum yield of fluorescence, (Φ_f,) ∼ 0.03, and fluorescence lifetime, (τ_f) ∼ 8 ns, and as a non-fluorescent aggregate. The proportion of monomeric form is higher in organic solvents and micelles but is reduced with increasing porphyrin concentrations in aqueous solutions. Porphyrin c readily complexes with Zn²⁺ to produce a fluorescent chelate (Zn-P c ) with Φ_f, ∼ 0.02 and τ_f, ∼ 2 ns at pH 7.5. The yields of singlet excited oxygen formation from Pc and the Zn-P c complex are higher than observed for hematoporphyrin derivative (HpD). Both P c and Zn-P c are effective agents in tumor phototherapy and do not induce the prolonged cutaneous photosensitivity observed with the use of HpD.     

A Remarkable Two-Step Synthesis of Diverse 1,4-Benzodiazepine-2,5-diones Using the Ugi Four-Component Condensation

A two-step, general synthesis of 1,4-benzodiazepine-2,5-diones (BZDs) is presented. This synthesis employs an Ugi four-component condensation using a convertible isocyanide (1-isocyanocyclohexene), followed by an acid-activated cyclization reaction. This synthesis represents a dramatically improved route to BZDs over those currently in the literature. In addition, since amino acids are not used as inputs, the potential for molecular diversity is much greater than that with existing syntheses. It was also found that BZDs substituted with methylenes at the C-3 and N-4 positions display conformational isomerism in the NMR spectra at room temperature. Variable-temperature NMR experiments support this observation and offer the interesting conclusion that the BZD core structure, in certain examples, might not be as rigid as previously supposed.     

Valence bond studies of AH2 molecules

Minimal basis set (STO) molecular orbital and valence-bond calculations are reported for the³ B ₁ and¹ A ₁ states of CH₂. The open-shell molecular orbital calculations used the Roothaan formulation. The valence-bond calculations used the Prosser-Hagstrom biorthogonalisation technique to evaluate the cofactors required in using Löwdin's formulae. Optimisation of geometry and orbital exponents in the molecular orbital calculation on the³ B ₁ state gave a geometry of R_C-H=2.11 a.u. and H-C-H=123.2 °. The energy obtained was ?38.8355 a.u. The molecular orbital and valencebond calculations are compared. In the valence-bond calculations the variation with bond-length and bond-angle of the configuration energies was studied. Valence bond “build-up” studies are also reported. Valence-bond calculations using hybrid orbitals instead of natural atomic orbitals showed that the perfect-pairing approximation is not as good for CH₂ as BeH₂. The nature of the lone-pair and bonding orbitals is found to be significantly different between the³ B ₁ and¹ A ₁ states. In the³ B ₁ state the 2s and 2p orbitals are fairly equally mixed between both types of orbital. However in the¹ A ₁ state the bonding orbitals have mainly 2p character and the lone pair orbitals have mainly 2s character. As was found for H₂O, the bonding hybrid orbitals do not follow the hydrogen nuclei as the bond angle varies but continue to point approximately in their equilibrium directions.     

Tetrakis(2-hydroxyphenyl)ethene and derivatives. A structurally preorganized tetradentate ligand system for polymetallic coordination chemistry and catalysis

A topologically unique, conformationally constrained tetradentate ligand system for polymetallic coordination chemistry has been developed: tetrakis(2-hydroxyphenyl)ethene (1a) and substituted derivatives. The design exploits the planarity of the tetraphenylethylene core to impart rigidity to the roughly square oxygen binding array, while maintaining a degree of conformational mobility associated with rotation about the aryl-ethylene carbon-carbon bonds. Tetrakis(2-hydroxyphenyl)ethene derivatives are designed to promote multiple metal bridging over chelating coordination modes. The ligand is synthesized from anisole or 4-tert-butylanisole in four steps via the 2,2'-dimethoxybenzophenone hydrazones 4a,b. The sterically hindered ortho-substituted tetraphenylethylene core is produced in high yield by acid-catalyzed decomposition of the corresponding diaryl diazomethane prepared in situ by oxidation of the hydrazone using nickel peroxide. Deprotection of the methyl ethers using boron tribromide gives tetrakis(2-hydroxyphenyl)ethene (1a), characterized by X-ray crystallography, and tetrakis(5-tert-butyl-2-hydroxyphenyl)ethene (1b). Sterically isolating substituents in the 3-position can be installed via Claisen rearrangement/hydrogenation, providing tetrakis(3-n-propyl-2-hydroxyphenyl)ethene (6) efficiently. To illustrate potential applications of this unprecedented ligand class, two coordination complexes are reported, including tetrakis(2-diethylaluminoxyphenyl)ethene (8), a structurally robust eight-membered-ring aluminum/oxygen crown complex characterized both in solution and in the solid state.     

Base-assisted intramolecular 6-acetoxypyranone-acetylene [5+2] cycloaddition. Synthesis and reactivity of novel oxa-tricyclo[5.3.1.0]undecenones

The synthesis of 3,11-dioxatricyclo[5.3.1.0^1,5]undeca-5,9-dien-8-ones is reported from suitable 5-substituted furfuryl alcohols bearing an acetylenic side-chain. Successive peracid-mediated oxidative rearrangement of furan carbinols and base-assisted intramolecular 1,3-dipolar cycloaddition afforded oxygen-bridged tricyclo-undecane derivatives. Stereoselective transformations of cycloadducts are also discussed.     

Dissociation of sulfur dioxide by ultraviolet multiphoton absorption between 224 and 232 nm

Multiphoton excitation and dissociation of SO(2) have been investigated in the wavelength range from 224 to 232 nm. Strong evidence is found for two-photon excitation to the H Rydberg state, followed by dissociation to SO + O and ionization of the SO product by absorption of a third photon. The two-photon excitation is resonantly enhanced via the C (1)B(2) intermediate state, and the two-photon yield spectrum thus bears a strong resemblance to the spectrum of this intermediate. Imaging of the O((3)P(2)), S((1)D(2)), and SO products suggests that, following dissociation of SO(2) from the H state, SO is produced in the A and B electronic states. S((1)D(2)) is produced both from two-photon dissociation of SO(2) to give S((1)D(2)) + O(2) and by single-photon dissociation of SO(+). In the former process, the O(2) is likely formed in all of its lowest three electronic states.     

Efficient and fast Heck vinylation of 2-bromo-6-methyl pyridines with methylacrylate. Application to the synthesis of 6-methyl cyclopenta[b]pyridinone

Heck vinylation of 2-bromo-6-methyl-3-substituted pyridines using η³-allylpalladium chloride dimer/P(o-Tol)₃ complex/toluene and dimethylacetamide (DMA) as co-solvent with methyl acrylate is reported. Electronic and steric effects were investigated engaging diversely 2-bromo-3,6-disubstituted pyridines. As application, a new synthesis of the 6-methyl cyclopenta[b]pyridinone building-block connecting Heck vinylation, alkene reduction and Dieckmann condensation is described.     

Bis(fluoroalkyl)acrylic and methacrylic phosphate monomers, their polymers and some of their properties

Ten fluoromonomers of structure (R_FO)₂P(O)OCH₂CH₂OC(O)CRCH₂ were made in 30-64% yield by treating the chloridates (R_FO)₂P(O)Cl with HOCH₂CH₂OC(O)CRCH₂ in chloroform in the presence of triethylamine [R_F=CF₃CH₂, C₂F₅CH₂, C₃F₇CH₂, C₄F₉CH₂, C₄F₉CH₂CH₂ or C₆F₁₃CH₂CH₂; R  H or Me]. The chloromonomer (CCl₃CH₂O)₂P(O)OCH₂CH₂OC(O)CHCH₂ was obtained analogously in 29% yield. Polymerisation of the acrylate monomers, but not the methacrylate monomers, could be effected using α-azoisobutyronitrile as a radical initiator. Acrylic polymers having CF₃CH₂O, CCl₃CH₂O and C₆F₁₃CH₂CH₂O side-chains were obtained as translucent rubbers. Specimens of cotton fabric were treated with solutions of the polymers, and average water and oil repellency ratings measured. Fabric coated with the polymer with the C₆F₁₃CH₂CH₂O side-chain afforded protection from penetration of the test liquids. Treated fabrics were subjected to the limiting oxygen index (LOI) test according to BS EN ISO 4589-2 (1999): this test determines the point at which a material just burns in a volumetric flow of oxygen and nitrogen. The treated fabrics were more fire-resistant (LOI 22-29%) than the untreated fabric (LOI 18%). Fabric coated with the CCl₃CH₂O-based polymer can be considered fire-retardant (LOI 29%). The fluoromonomers were tested for anti-acetylcholinesterase activity and were found to be poor enzyme inhibitors; they are predicted to possess low acute toxicity.     

Effect of the sixth axial ligand in CS-ligated iron(II)octaethylporphyrinates: structural and Mössbauer studies

The effect of a sixth ligand in a series of low-spin thiocarbonyl-ligated iron(II)octaethylporphyrinates has been investigated. Six-coordinate complexes have been synthesized and characterized by M?ssbauer and infrared spectroscopy and single-crystal X-ray structure determinations. The results are compared with the five-coordinate parent complex. The crystal structures of [Fe(OEP)(CS)(1-MeIm)] and [Fe(OEP)(CS)(Py)] are reported and discussed. The 1-methylimidazole and pyridine derivatives exhibit Fe-C(CS) bond distances of 1.703(4) and 1.706(2) A that are significantly longer than the 1.662(3) A reported for five-coordinate [Fe(OEP)(CS)] (Scheidt, W. R.; Geiger, D. K. Inorg. Chem. 1982, 21, 1208). The trans Fe-N(ligand) distances of 2.112(3) and 2.1550(15) A observed for the 1-methylimidazole and pyridine complex are approximately 0.13 A longer than those observed for analogous bis-ligated complexes and are consistent with a significant structural trans effect for the CS ligand. M?ssbauer investigations carried out for five- and six-coordinate thiocarbonyl derivatives with several different sixth axial ligands reveal interesting features. All derivatives exhibit very small isomer shift values, consistent with a very strong interaction between iron and CS. The five-coordinate derivative has delta(Fe) = 0.08 mm/s, and the six-coordinate complexes exhibit delta(Fe) = 0.14 to 0.19 mm/s at 4.2 K. The five-coordinate complex shows a large quadrupole splitting (DeltaE(q) = 1.93 mm/s at 4.2 K) which is reduced on coordination of the sixth ligand (DeltaE(q) = 0.42-0.80 mm/s at 4.2 K). Addition of a sixth ligand also leads to a small decrease in the value of nu(CS). Correlations in structural, IR, and M?ssbauer results suggest that the sixth ligand effect is primarily induced by changes in sigma-bonding. The structure of [Fe(OEP)(CS)(CH(3)OH)] is briefly reported. Crystal data: [Fe(OEP)(CS)(1-MeIm)] crystallizes in the monoclinic system, space group P2(1)/n, Z = 4, a = 9.5906(5) A, b = 16.704(4) A, c = 23.1417(6) A, beta = 100.453(7) degrees. [Fe(OEP)(CS)(Py)] crystallizes in the triclinic system, space group P1, Z = 5, a = 13.9073(6) A, b = 16.2624(7) A, c = 22.0709(9) A, alpha = 70.586(1) degrees, beta = 77.242(1) degrees, gamma = 77.959(1) degrees. [Fe(OEP)(CS)(CH(3)OH)] crystallizes in the triclinic system, space group P1, Z = 1, a = 9.0599(5) A, b = 9.4389(5) A, c = 11.0676(6) A, alpha = 90.261(1) degrees, beta = 100.362(1) degrees, gamma = 114.664(1) degrees.     

Aziridinomitosenes by anionic cyclization: deuterium as a removable blocking group

Treatment of 11a with methyllithium affords the destannylated product 12 together with a small amount of tetracyclic product derived from intramolecular Michael addition. The same procedure from the deuterated analogue 11b gives the tetracyclic 18 as the major product, the result of a substantial kinetic deuterium isotope effect that favors formation of 16 and 17 by suppressing indole ring lithiation to the undesired 15. When the product mixture is quenched with phenylselenenyl chloride, 17 is converted into the aziridinomitosene 19 in 80% yield. Conversion into the aziridinomitosene alcohol 21 and the deprotected aziridine 20 is also demonstrated.