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Synthesis and evaluation of potential N-pi and N-sigma metal chelation sites within the beta-hydroxy-L-histidine subunit of bleomycin A(2): Functional characterization of imidazole N-pi metal complexation

Academic Article
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Overview

related to degree

  • Cai, Hui, Ph.D. in Chemistry, Scripps Research 1994 - 1999

authors

  • Boger, Dale
  • Ramsey, T. M.
  • Cai, Hui

publication date

  • February 1996

journal

  • Bioorganic & Medicinal Chemistry  Journal

abstract

  • The synthesis and evaluation of 4 and 5, fully functionalized deglycobleomycin A2 (2) analogues incorporating an oxazole and a pyrrole in place of the beta-hydroxy-L-histidine imidazole, are detailed. The oxazole agent is only capable of Npi metal complexation through a form related to the N1-H imidazole tautomer of bleomycin A2 (1) while the pyrrole agent may potentially mimic the Nsigma metal complexation capabilities of the imidazole N3-H tautomer. Metal complexes (Fe-II, Fe-III) of 4 and 5 were found to cleave duplex DNA in the presence of O2 (Fe-II) or H2O2 (Fe-III). The oxazole agent 4 which is incapable of Nsigma metal chelation was found to behave analogous to, albeit slightly less effectively than, deglycobleomycin A2 resulting in the characteristic 5'-GC/5'-GT sequence selective cleavage of duplex DNA directly confirming that imidazole/oxazole Npi metal chelation is sufficient for functional reactivity. Importantly, the effective substitution of the oxazole O-1 for the histidine N-1 further illustrates that this group does not require deprotonation upon metal complexation, oxygen activation, or the ensuing oxidation reactions, that the functional bleomycin A2 tautomer is the imidazole N'-H tautomer, and that the imidazole N'-H functionality is not contributing to the polynucleotide recognition through H-bonding to the phosphate backbone or nucleotide bases. In contrast, the pyrrole agent 5 which is incapable of Npi metal chelation, but possesses the capabilities of functioning as a Nsigma metal donor was also found to cleave duplex DNA, but does so in a nonsequence selective fashion with a significantly reduced efficiency and a diminished double to single strand cleavage ratio both only slightly above that of background iron itself. These observations are analogous to those made with 3 which lacks the imidazole altogether and further support the observations that Nsigma coordination, not Npi coordination, of the imidazole is required for the functional activity of bleomycin A2.

subject areas

  • Antimetabolites, Antineoplastic
  • Autoradiography
  • Base Sequence
  • Binding Sites
  • Bleomycin
  • Chelating Agents
  • Cloning, Molecular
  • DNA
  • DNA, Superhelical
  • Electrophoresis, Polyacrylamide Gel
  • Histidine
  • Hydroxylation
  • Molecular Sequence Data
  • Structure-Activity Relationship
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Identity

International Standard Serial Number (ISSN)

  • 0968-0896

Digital Object Identifier (DOI)

  • 10.1016/0968-0896(95)00184-0

PubMed ID

  • 8814878
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Additional Document Info

start page

  • 195

end page

  • 207

volume

  • 4

issue

  • 2

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