Haem oxygenase-1 (HO1) is a heat-shock protein that is induced by stressful stimuli. Here we demonstrate a cytoprotective role for HO1: cell death produced by serum deprivation, staurosporine or etoposide is markedly accentuated in cells from mice with a targeted deletion of the HO1 gene, and greatly reduced in cells that overexpress HO1. Iron efflux from cells is augmented by HO1 transfection and reduced in HO1-deficient fibroblasts. Iron accumulation in HO1-deficient cells explains their death: iron chelators protect HO1-deficient fibroblasts from cell death. Thus, cytoprotection by HO1 is attributable to its augmentation of iron efflux, reflecting a role for HO1 in modulating intracellular iron levels and regulating cell viability.

The binding of enantiomers of Ru(bpy)2(ppz)2+ (bpy = 2,2'-bipyridine; ppz = 4,7-phenanthrolino[6,5-b]-pyrazine) to calf thymus DNA is investigated using absorption, fluorescence and resonance enhanced Raman spectroscopies. Both isomers show absorption hypochromicity, steady-state fluorescence increase, reduced accessibility to an anionic quencher, and fluorescence lifetime increase associated with binding to B-form DNA, though the effect for the A isomer is always less. However, the maximal fluorescence polarization for both isomers is the same, indicating a similarly rigid binding to DNA. These findings are consistent with a major groove binding in which the ppz ligand is partially intercalated for both enantiomers. The bpy ligands are relatively small and not competent for inducing intercalative binding, but enantioselectivity is maintained by the differential interactions of these bpy ligands with the surface of the major groove as the ppz ligand partially intercalates.The binding to DNA, RNA, and synthetic polynucleotides of cationic tris-chelatesof ruthenium(I1) and rhodium(II1) in which the ligands are bidentate diimines with aromatic ring structures has been extensively studied'-'2J7J9 in recent years. An intercalative mode of binding, in which a portion of one of the three chelated aromatic rings inserts between adjacent base pairs of the native DNA structure via major groove access, is a key component of models which have been p r~p o s e d~,~*~, * J~J~ to describe the binding of such complex ions to polynucleotides. In particular, intercalative major groove binding is consistent with and provides a rational basis for the observation that enantioselectivity is a feature of the binding of many such complex ions to these polynucleotides.Although numerous complexes of this type have been shown to bind enantioselectively, only a few reports have appeared3-sJ3 which detail the interactions of individual enantiomers with DNA or other polynucleotides, principally for R~( p h e n )~~+ (phen = 1,lO-phenanthroline) and trisphenanthroline complexes of Rh3+, C03+, N?+, and Cr3+. Barton et al. have studiedl-3Jv6 the binding of A-and A -R~( p h e n )~~+ to various DNA's and homopolynucleotides, mainly poly(dG4C) in both B-and Z-forms. An analysis of spectroscopic and photophysical evidence leads them to the conclusion that the favored binding of the A isomer within the major groove of B-form DNA is explained by an intercalative binding mode of one of the phen ligands with the other two coordinated phens establishing a pattern of van der Waals contacts with atoms lining the major groove, providing a better "fit" for the A isomer. Similar binding of the A isomer within the major groove is more sterically disfavored. In binding studies3 of the enantiomers of Ru(DIP)3Z+ (DIP = 4,7-diphenylphenanthroline), the same group concluded that binding of the A isomer of this complex to the left-handed helical Z-form poly(dGC) was favored via a similar (complementary) mechanism. NMR studies by the Barton group6 have not provided co...

Formation of a DNA-bound heterobimetallic complex involving Ru(bpy)2tpphz2+ (tpphz = tetrapyrido[3,2-a:2‘,3‘-c:3‘ ‘,2‘ ‘-h:2‘ ‘,3‘ ‘-j]phenazine) and Cu2+ is proposed. The monomeric Ru(bpy)2tpphz2+ is highly luminescent in B-DNA at [DNA-P]/[Ru] = 50, 10 μM Ru. Upon addition of Cu2+, luminescence loss and spectral shifts consistent with Cu2+ complexation and strong associational quenching are observed. Formation of a Ru(bpy)2tpphz2+/Cu2+ DNA complex which places one metal center in the major groove and the other in the minor groove on the opposing side of the helical axis is proposed.

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The syntheses and properties of three new ruthenium(I1) complexes based on the ligand 2,2':4,4":4',4'"-quaterpyridyl (qpy) are reported. Each new complex is of the type [R~(bpy),L]~, where L is the parent qpy ligand or is qpy derivatized by the methylation of one or both of the non-a-diimine nitrogen atoms and n = 2,3, or 4. The photophysical and electrochemical properties of the new complex ions are reported. The parent ion [R~(bpy)~qpy]~+ is strongly luminescent and has a relatively long lifetime, e.g. in excess of 1400 ns in acetonitrile solution. In contrast, the lifetime of the dimethyl derivative [Ru(bpy),(qpyme,)14+ is less than 100 ns. This dimethylated complex has some novel properties. The excited state produced by M-L excitation to the qpyme? ligand can be considered in terms of a Ru(II1) core and a positively charged ligand. Typically, the excited states of other ruthenium(I1) diimine complexes have had neutral or negatively charged ligands. Further, in structural terms, the complex can be considered as an intramolecular assembly of a ruthenium(I1) diimine site and a viologen site. Cyclic voltammetry indicates that the first two electrons added to the complex enter the viologen-like acceptor site constituted by the qpyme?+ ligand.