METALLOPURPURINS and LIGHT: EFFECT ON TRANSPLANTABLE RAT BLADDER TUMORS and MURINE SKIN

Purpurins are modified chlorins with photodynamic properties. Their strong absorption in the red region of the visible spectrum makes them candidates for use in photodynamic cancer therapy. A series of metal derivatives of the free base purpurins have been synthesized and shown to cause tumor necrosis in transplantable tumors when exposed to visible light. In the following set of experiments, the effects of two metallo-derivatives (tin and zinc) of two purpurins, octaethylpurpurin (NT2) and etiopurpurin (ET2), and light on the N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide transplantable tumors in Fischer CDF(F344)/CrlBr rats were studied. The photodynamic activity was assessed by a short term assay using tumor dry weight 12 days after purpurin-PDT as a criterion of response. From these experiments it appears that SnET2 greater than SnNT2 greater than ZnET2 greater than ZnNT2 in photodynamic activity. SnET2 was further characterized by attempting to determine the time interval after systemic injection at which maximum therapeutic effect occurred. These studies shown that 24 h after metallopurpurin injection was the optimum time for treatment of tumors with visible light. In a final set of experiments, the effect of solar light on the skin of hairless mice injected with SnET2 was found to be much less injurious than with hematoporphyrin derivative.     

THE REACTIVITY OF SUPEROXIDE (O2-) and ITS ABILITY TO INDUCE CHEMILUMINESCENCE WITH LUMINOL

Abstract— The quantum yield and the kinetics of O -induced luminol chemiluminescence was investigated in a broad pH interval at varying luminol and concentrations. It is suggested that the weak chemiluminescence observed is mediated via a luminol-superoxide-adduct proposed to be an a-hydroxyperoxyl radical. At pH 7 the maximum quantum yield of chemiluminescence per initial percent was determined to be 4 times 10^-8. The degree of involvement in phagocytosis and related processes should be viewed against this maximum limit.     

Oxidative Addition of Haloheteroarenes to Palladium(0): Concerted versus SNAr‐Type Mechanism

The kinetics of the oxidative additions of haloheteroarenes HetX (X=I, Br, Cl) to [Pd⁰(PPh₃)₂] (generated from [Pd⁰(PPh₃)₄]) have been investigated in THF and DMF and the rate constants have been determined. In contrast to the generally accepted concerted mechanism, Hammett plots obtained for substituted 2‐halopyridines and solvent effects reveal a reaction mechanism dependent on the halide X of HetX: an unprecedented S_NAr‐type mechanism for X=Br or Cl and a classical concerted mechanism for X=I. These results are supported by DFT studies.     

Switching the Switch: Ligand Induced Disulfide Formation in HDAC8

Human histone deacetylase 8 is a well-recognized target for T-cell lymphoma and particularly childhood neuroblastoma. PD-404,182 was shown to be a selective covalent inhibitor of HDAC8 that forms mixed disulfides with several cysteine residues and is also able to transform thiol groups to thiocyanates. Moreover, HDAC8 was shown to be regulated by a redox switch based on the reversible formation of a disulfide bond between cysteines Cys₁₀₂ and Cys₁₅₃. This study on the distinct effects of PD-404,182 on HDAC8 reveals that this compound induces the dose-dependent formation of intramolecular disulfide bridges. Therefore, the inhibition mechanism of HDAC8 by PD-404,182 involves both, covalent modification of thiols as well as ligand mediated disulfide formation. Moreover, this study provides a deep molecular insight into the regulation mechanism of HDAC8 involving several cysteines with graduated capability to form reversible disulfide bridges.