Rapid initiation of apoptosis can be induced by photodynamic therapy, depending on the cell line and sensitizer employed. In this study, we evaluated the photodynamic responses to two structurally related photosensitizing agents, using the P388 murine leukemia cell line in culture. Photodamage mediated by tin etiopurpurin involved lysosomes and mitochondria and yielded a rapid apoptotic response; apoptotic nuclei were observed within 60 min after PDT. A drug analog, tin octaethylpurpurin amidine, targeted lysosomes, mitochondria and cell membranes; apoptotic nuclei were not observed until 24 h after PDT. These results, together with other recent reports, are consistent with the hypothesis that membrane photodamage can delay or prevent an apoptotic response to PDT.

Dicobalt(II) cofacial bisporphyrins anchored by dibenzofuran (DPD) and xanthene (DPX) are efficient electrocatalysts for the four-electron reduction of oxygen to water despite their ca. 4 Å difference in metal-metal distances, suggesting that the considerable longitudinal 'Pac-Man' flexibility of the pillared platforms is the origin for the similar catalytic reactivity of these structurally disparate systems.Enzymatic systems are remarkable in their ability to accommodate the large range of motion required for the binding and catalysis of small molecules. In many cases, the kinetic steps of the processes involved are ultimately predicated on conformational changes of the active site upon substrate binding, activation, and/or product release. An outstanding example is the binding and biological reduction of dioxygen to water by cytochrome c oxidase (CcO). 1 The critical O-O bond cleavage chemistry is mediated by a flexible, dinuclear iron-heme/ copper (Fe a3 /Cu B ) assembly. 1,2 Nevertheless, the pursuit of structural and functional models for O 2 activation have emphasized, for the most part, bimetallic reaction centers poised within well-defined, rigid pockets. [3][4][5][6][7] For example, pillared cofacial dicobalt bisporphyrins bridged by anthracene (DPA) and biphenylene (DPB) 8-11 impair ring slippage, and as a result, these complexes efficiently electrocatalyze the direct fourelectron reduction of oxygen to water (as opposed to the twoelectron pathway involving peroxide) with little structural reorganization of juxtaposed subunits. Can efficient oxygenactivation chemistry be preserved when this cofacial structural motif exhibits a large range of motion? To address this issue, we have developed methods for the facile assembly of new cofacial bisporphyrins, incorporating dibenzofuran (DPD) 12 or xanthene (DPX) 13 pillars that exhibit variable pocket sizes with minimal lateral displacements. Herein, we report that dicobalt(II) complexes of both DPD and DPX efficiently mediate the direct four-electron reduction of oxygen to water despite a ca. 4 Å difference in their metal-metal distances (as determined from their X-ray crystal structures), suggesting that the longitudinal 'Pac-Man' flexibility of these molecular clefts allows the designed binding pocket to structurally accommodate reaction intermediates during multielectron catalysis.Co 2 (DPD) 1 was obtained in excellent yield (91%) from reaction of the corresponding free base bisporphyrin with CoCl 2 and 2,6-lutidine. † Crystals suitable for X-ray diffraction studies were grown from dichloromethane-methanol solutions. ‡ The structure of 1 (Fig. 1) shows that two methanol solvent molecules are coordinated inside the bisporphyrin pocket to the two cobalt(II) centers. In order to accommodate the two exogeneous ligands, the DPD framework opens its 'bite' considerably. The interplanar angle between the two macrocycles is 56.5°, resulting in metal-metal (8.624 Å) and centerto-center (8.874 Å) distances that are markedly larger than found in Zn 2 (DPD) (d Zn-Zn = ...

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A comparison of the structure, spectroscopy, and oxygen atom-transfer reactivity of cofacial bisporphyrins anchored by xanthene (DPX) and dibenzofuran (DPD) pillars is presented. The synthesis and characterization of dicopper(II) and dinickel(II) complexes of DPD completes a homologous series of homobimetallic zinc(II), copper(II), and nickel(II) complexes for both cofacial platforms. X-ray crystallographic analysis of the parent free-base porphyrins H(4)DPX (1) and H(4)DPD (5) confirms the face-to-face arrangement of the two porphyrin macrocycles with a large available range of vertical pocket sizes: 1 (C(80)H(92)Cl(2)N(8)O), triclinic, space group P1 macro, a = 13.5167(12) A, b = 21.7008(18) A, c = 23.808(2) A, alpha = 80.116(2) degrees, beta = 76.832(2) degrees, gamma = 80.4070(10) degrees, Z = 4; 5 (C(80)H(83)N(8)O(2)), monoclinic, space group C2/c, a = 22.666(2) A, b = 13.6749(14) A, c = 42.084(4) A, beta = 94.554(2) degrees, Z = 8. EPR spectroscopy of dicopper(II) derivatives Cu(2)DPX (3) and Cu(2)DPD (7) complements the crystallographic studies by probing intramolecular metal-metal arrangements in frozen solution. Exciton interactions between the porphyrin subunits in fluid solution are revealed by steady-state and time-resolved electronic absorption and emission spectroscopy. The resulting compilation of structural and spectroscopic data provides a benchmark for the use of these and related platforms for the activation of small-molecule substrates. A structure-function relation is developed for the photoinduced oxygen atom-transfer reactions of bisiron(III) mu-oxo derivatives of DPX and DPD. The efficiency of the photochemical process is markedly dependent (approximately 10(4)-fold) on the vertical flexibility of cofacial architecture provided by the spacer.

The synthesis and characterization of cofacial bisporphyrins juxtaposed by xanthene-bridged pillars are presented. The one-pot preparation of the xanthene dialdehyde avoids the lengthy bridge synthesis accompanying other cofacial porphyrin systems, thus allowing for the facile preparation of homobimetallic zinc (10), copper (11), and nickel (12) complexes. The cofacial orientation of the two porphyrin macrocycles was confirmed by X-ray crystallography. Structural data are provided for bisporphyrins 10-12: 10 (C79H82N8OZn2), triclinic, space group P1, a = 11.2671(2) A, b = 14.9809(2) A, c = 20.4852(2) A, alpha = 101.6680(10) degrees, beta = 100.8890(10) degrees, gamma = 101.8060(10) degrees, Z = 2; 11 (C79H82N8OCu2), triclinic, space group P1, a = 11.21410(10) A, b = 14.9539(5) A, c = 20.6915(7) A, alpha = 101.810(2) degrees, beta = 101.044(2) degrees, gamma = 101.722(2) degrees, Z = 2; 12 (C79H82N8ONi2), monoclinic, space group C2/c, a = 24.1671(4) A, b = 10.669 A, c = 50.5080(9) A, beta = 99.553(2) degrees, Z = 8. Exciton interactions between the porphyrin rings are apparent in electronic spectra, consistent with the cofacial superstructure. The combination of structural and spectroscopic data provides a basis for the design of additional metal derivatives for the activation of dioxygen and other small molecules.

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., and NIH (P01 CA168585 and R35 CA197633).

Due to the tolerance of catalyst 7 in combination with the interesting properties of poly(DCPD), new filled or unfilled thermosets could be prepared, which should find novel applications in the field of electro casting, insulation, and tooling (among others) in the near future. Work to improve catalysts and polymer systems are ongoing. Experimental SectionThe ruthenium and osmium complexes were prepared according to literature procedures [ll]. NBE was purchased from Fluka, and DCPD (technical quality, 94%) from Shell and used as received. Viscosimetric measurements were performed on a home-built, real-time viscosimeter. Gel times were recorded on a Brookfield viscosimeter, DSCs on a Mettler DSC30 with a Mettler TCll controller, TGAs on a Mettler TG50 with a Mettler TCfOA controller, and surface roughness on a Form Talysurf S3C-50. Micro hardness was determined on a Fischerscope H100. I3C CP-MAS NMR spectra of a piece of poly(DCPD) that was tightly fitted into the spinner were recorded on a Bruker 400-MHz instrument with a MAS rate of 11 kHz and a pulse delay of 5 s (a pulse delay of 60 s gave an identical result).

An affinity-based mass spectrometry screening technology was used to identify novel binders to both nonphosphorylated and phosphorylated ERK2. Screening of inactive ERK2 identified a pyrrolidine analogue 1 that bound to both nonphosphorylated and phosphorylated ERK2 and inhibited ERK2 kinase activity. Chemical optimization identified compound 4 as a novel, potent, and highly selective ERK1,2 inhibitor which not only demonstrated inhibition of phosphorylation of ERK substrate p90RSK but also demonstrated inhibition of ERK1,2 phosphorylation on the activation loop. X-ray cocrystallography revealed that upon binding of compound 4 to ERK2, Tyr34 undergoes a rotation (flip) along with a shift in the poly-Gly rich loop to create a new binding pocket into which 4 can bind. This new binding mode represents a novel mechanism by which high affinity ATP-competitive compounds may achieve excellent kinase selectivity.