Ni(II)·Arg-Gly-His−DNA Interactions:  Investigation into the Basis for Minor-Groove Binding and Recognition

Fang, Yayin; Ray, Bruce D.; Claussen, Craig A.; Lipkowitz, Kenny B.; Long, Eric C.

doi:10.1021/ja049875u

Cited by 55 publications

(65 citation statements)

References 47 publications

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“…However, the exact role of metal ion coordination in the mechanism of action of UK-1 and analogs remains to be determined. There is a growing interest in the role of metal ions and their complexes in drug design [11][12][13][14], particularly in metal complex-DNA interactions [15][16][17][18][19][20][21]. Studies of UK-1 and its analogs may offer important insights, provided by nature, into how metal ion complexation can be harnessed in the design of selective cytotoxins.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, metal ion binding, and biological evaluation of new anticancer 2-(2′-hydroxyphenyl)benzoxazole analogs of UK-1

McKee¹,

Kerwin²

2008

Bioorganic & Medicinal Chemistry

165

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UK-1 is a bis(benzoxazole) natural product displaying activity against a wide range of human cancer cell lines. A simplified analog of UK-1, 4-carbomethoxy-2-(2'-hydroxyphenyl)benzoxazole, was previously found to be almost as active as UK-1 against cancer cell lines, and similar to the natural product, formed complexes with variety of metal ions such as Mg 2+ and Zn 2+ . A series 4-substituted-2-(2'-hydroxyphenyl)benzoxazole analogs of this "minimal pharmacophore" of UK-1 were prepared. The anti-cancer activity of these analogs was examined in breast and lung cancer cell lines. Spectrophotometric titrations in methanol were carried out in order to assess the ability of UK-1 and these analogs to coordinate with Mg 2+ and Cu 2+ ions. Although none of the new analogs were more cytotoxic than 4-carbomethoxy-2-(2'-hydroxyphenyl)benzoxazole, some analogs were identified that display similar cytotoxicity to this simplified UK-1 analog with improved water solubility. UK-1 and all of these new analogs bind Cu 2+ ions better than Mg 2+ ions, and the nature of the 4-substituent is important for the Mg 2+ ion binding ability of these 2-(2'-hydroxyphenyl) benzoxazoles. Previous studies of a limited number of UK-1 analogs demonstrated a correlation between Mg 2+ ion binding ability and cytotoxicity; however, within this series of 4-substituted-2-(2'-hydroxyphenyl)benzoxazoles the variations in cytotoxicity do not correlate with either Mg 2+ or Cu 2+ ion binding ability. These results, together with recent ESI-MS studies of Cu 2+ -mediated DNA binding by UK-1 and analogs, indicate that UK-1 and analogs may exert their cytotoxic effects by interaction with Cu 2+ or other transition metal ions, rather than Mg 2+ , and that metal ion-mediated DNA binding, rather than metal ion binding affinity, is important for the cytotoxic effect of these compounds. The potential role of Cu 2+ ions in the cytotoxic action of UK-1 is further supported by observation that UK-1 in the presence of Cu 2+ displays enhanced cytotoxicity to MCF-7 and A549 cells when compared to UK-1 alone.

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Section: Introductionmentioning

confidence: 99%

Synthesis, metal ion binding, and biological evaluation of new anticancer 2-(2′-hydroxyphenyl)benzoxazole analogs of UK-1

McKee¹,

Kerwin²

2008

Bioorganic & Medicinal Chemistry

165

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“…Several other papers have used modelling studies to interpret experimental data on DNA/transition-metal complexes, [17,21] but since their emphasis was on understanding the experimental data, these calculations again omitted the solvent. Rigorous molecular dynamics simulations with explicit solvent have been performed for cobaltA C H T U N G T R E N N U N G (iii)-hexammine [22] and a nickel(ii)-metalloprotein [23] in the presence of DNA. In both cases, the simulations produced good agreement with a range of experimental data; in neither case was there significant bending or coiling of DNA.…”

Section: Introductionmentioning

confidence: 99%

Simulations of DNA Coiling around a Synthetic Supramolecular Cylinder That Binds in the DNA Major Groove

Khalid

Hannon

Rodger

et al. 2006

Chemistry A European J

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In this work we present the results of a molecular simulation study of the interaction between a tetracationic bis iron(II) supramolecular cylinder, [Fe2(C25H20N4)3]4+, and DNA. This supramolecular cylinder has been shown to bind in the major groove of DNA and to induce dramatic coiling of the DNA. The simulations have been designed to elucidate the interactions that lead the cylinder to target the major groove and that drive the subsequent DNA conformational changes. Three sets of multi-nanosecond simulations have been performed: one of the uncomplexed d(CCCCCTTTTTCC) d(GGAAAAAGGGGG) dodecamer; one of this DNA complexed with the cylinder molecule; and one of this DNA complexed with a neutralised version of the cylinder. Coiling of the DNA was observed in the DNA-cylinder simulations, giving insight into the molecular level nature of the supramolecular coiling observed experimentally. The cylinder charge was found not to be essential for the DNA coiling, which implies that the DNA response is moderated by the short range interactions that define the molecular shape. Cylinder charge did, however, affect the integrity of the DNA duplex, to the extent that, under some circumstances, the tetracationic cylinder induced defects in the DNA base pairing at locations adjacent to the cylinder binding site.

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“…6C, D, M = Cu) were estimated according to Fang et al (2004) and briefl y confi rmed by molecular orbital calculations (unpublished results).…”

Section: Designing Novel Biocatalystsmentioning

confidence: 99%

Copper-Binding Peptides from Human Prion Protein and Newly Designed Peroxidative Biocatalysts

Kagenishi

Yokawa

Kadono

et al. 2011

Zeitschrift Für Naturforschung C

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A previous work suggested that peptides from the histidine-containing copper-binding motifs in human prion protein (PrP) function as peroxidase-like biocatalysts catalyzing the generation of superoxide anion radicals in the presence of neurotransmitters (aromatic monoamines) and phenolics such as tyrosine and tyrosyl residues on proteins. In this study, using various phenolic substrates, the phenol-dependent superoxide-generating activities of PrP-derived peptide sequences were compared. Among the peptides tested, the GGGTH pentapeptide was shown to be the most active catalyst for phenol-dependent reactions. Based on these results, we designed a series of oligoglycyl-histidines as novel peroxidative biocatalysts, and their catalytic performances including kinetics, heat tolerance, and freezing tolerance were analysed.

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Ni(II)·Arg-Gly-His−DNA Interactions: Investigation into the Basis for Minor-Groove Binding and Recognition

Cited by 55 publications

References 47 publications

Synthesis, metal ion binding, and biological evaluation of new anticancer 2-(2′-hydroxyphenyl)benzoxazole analogs of UK-1

Synthesis, metal ion binding, and biological evaluation of new anticancer 2-(2′-hydroxyphenyl)benzoxazole analogs of UK-1

Simulations of DNA Coiling around a Synthetic Supramolecular Cylinder That Binds in the DNA Major Groove

Copper-Binding Peptides from Human Prion Protein and Newly Designed Peroxidative Biocatalysts

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