Evaluation of complexes of DNA duplexes and novel benzoxazoles or benzimidazoles by electrospray ionization mass spectrometry

Oehlers, Leon P.; Mazzitelli, Carolyn L.; Brodbelt, Jennifer S.; Rodriguez, Mireya; Kerwin, Sean M.

doi:10.1016/j.jasms.2004.07.015

Cited by 47 publications

(46 citation statements)

References 46 publications

(37 reference statements)

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“…The key structural elements that affect metal binding and cytotoxicity were addressed by comparing 1 with its 7-substituted benzoxazole analog 3 ( Figure 1). Compound 3 differs with 1 solely in the disposition of the benzoxazole N and O atoms, but it is less cytotoxic than 1 [10]. In addition, the complexation of Mg 2+ by 1 and 3, as determined by 1 H NMR and ESI-mass spectra were quite distinct [10].…”

Section: Analog Design and Synthesismentioning

confidence: 94%

“…Compound 3 differs with 1 solely in the disposition of the benzoxazole N and O atoms, but it is less cytotoxic than 1 [10]. In addition, the complexation of Mg 2+ by 1 and 3, as determined by 1 H NMR and ESI-mass spectra were quite distinct [10]. There was also minimal DNA-metal mediated binding of 3 compared to 1 observed by ESI-MS [10].…”

Section: Analog Design and Synthesismentioning

confidence: 95%

“…Recently, synthetic studies of analogs of UK-1 have been undertaken [4][5][6][7][8], and simplified analogs, such as the benzoxaole 1 ( Figure 1) have been identified that possess similar, selective cancer cell cytotoxicity to that of UK-1 [6][7][8]. Studies of UK-1 and these synthetic analogs have implicated metal ion complexation as an important factor in the activity of these agents [6][7][8][9][10]. UK-1 binds a variety of di-and trivalent metal ions, and binds to double-stranded DNA better in the presence of metal ions than in their absence [6,9,10].…”

Section: Introductionmentioning

confidence: 99%

“…Studies of UK-1 and these synthetic analogs have implicated metal ion complexation as an important factor in the activity of these agents [6][7][8][9][10]. UK-1 binds a variety of di-and trivalent metal ions, and binds to double-stranded DNA better in the presence of metal ions than in their absence [6,9,10]. Active anticancer analogs of UK-1, such as 1, also display this affinity for metal ions and metal-mediated DNA binding ability [6,10].…”

Section: Introductionmentioning

confidence: 99%

“…UK-1 binds a variety of di-and trivalent metal ions, and binds to double-stranded DNA better in the presence of metal ions than in their absence [6,9,10]. Active anticancer analogs of UK-1, such as 1, also display this affinity for metal ions and metal-mediated DNA binding ability [6,10]. In contrast, analogs such as 2 neither bind DNA in a metal ion-mediated fashion nor display cancer cell cytotoxicity [5,6].…”

Section: Introductionmentioning

confidence: 99%

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

McKee¹,

Kerwin²

2008

Bioorganic & Medicinal Chemistry

160

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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: Analog Design and Synthesismentioning

confidence: 94%

Section: Analog Design and Synthesismentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

McKee¹,

Kerwin²

2008

Bioorganic & Medicinal Chemistry

160

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Biological and Biomedical Aspects of Metal Phenolates

Ming

2014

Patai's Chemistry of Functional Groups

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The phenol functionality is involved in diverse biological processes and functions, serving as a proton donor and as a metal‐binding ligand. It is commonly found in many biochemicals (such as siderophores and the amino acids tyrosine and tryptophan), pharmaceuticals (including antibiotics, metal‐chelating agents, and diagnostic agents), and natural products (such as polyphenols, flavonoids, and salicylic acid). In association with other functional groups, the phenol moiety forms various types of metal‐binding sites of diverse structures and functions, for example, for iron binding and transport, in enzymes for oxygenation of substrates, and for biotransformation of aromatic compounds. Many environmentally hazardous aromatic compounds such as bisphenol A, PCB, and DDT can be degraded by tyrosinate(phenolate)‐containing metalloenzymes from microorganisms, which provides a clue for bioremediation of these toxic substances. Moreover, the phenol‐containing wet‐adhesive byssal proteins from some clams and mussels has stimulated further development of adhesive materials for medical and other applications; and the study of binding of transferrin with nanoparticles affords better understanding of protein–mineral interfacial interactions. In addition to these naturally occurring metal‐phenolate centers, there are many metal complexes of phenol and derivatives that exhibit various catalytic activities and serve as structural and/or functional model systems for tyrosinate‐containing metalloproteins.

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Evaluation of relative DNA binding affinities of anthrapyrazoles by electrospray ionization mass spectrometry

Smith

Guziec

et al. 2007

J. Mass Spectrom.

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Binding interactions of a new series of anthrapyrazoles (APs) with DNA were evaluated by electrospray ionization mass spectrometry (ESI-MS). Relative binding affinities were estimated from the ESI-MS data based on the fraction of bound DNA for DNA/anthrapyrazole mixtures, and they show a correlation to the shift in melting point of the DNA measured from a previous study. Minimal sequence specificity was observed for the series of anthrapyrazoles. Upon collisionally activated dissociation of the duplex/anthrapyrazole complexes, typically ejection of the ligand was the dominant pathway for most of the complexes. However, for complexes containing AP2 or mitoxantrone, strand separation with the ligand remaining on one of the single strands was observed, indicative of a different binding mode or stronger binding.

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Evaluation of complexes of DNA duplexes and novel benzoxazoles or benzimidazoles by electrospray ionization mass spectrometry

Cited by 47 publications

References 46 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

Biological and Biomedical Aspects of Metal Phenolates

Evaluation of relative DNA binding affinities of anthrapyrazoles by electrospray ionization mass spectrometry

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