Spectroscopic investigation of the metal ligation and reactivity of the ferrous active sites of bleomycin and bleomycin derivatives

Kelly E. Loeb, Jeffrey M. Zaleski, Cynthia D. Hess, Sidney Hecht, Edward I. Solomon

Research output: Contribution to journalArticle

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Abstract

The geometric and electronic structures of high-spin ferrous complexes of bleomycin (Fe11BLM) anti a series of systematically perturbed BLM derivatives have been investigated by optical absorption, circular dichroism (CD), and magnetic circular dichroism (MCD) spectroscopies. The active site of the unmodified drug complex is six- coordinate with the coordination sphere completed by at least five endogenous ligands including the pyrimidine, imidazole, deprotonated amide, and secondary and primary amine functionalities with either the 3-O-carbamoyl substituent of the mannose sugar or solvent bound at the sixth site. This weak sixth ligand is the exchangeable site of exogenous small molecule binding. Perturbing the carbamoyl substituent alters the coordination environment of the metal and decreases the azide binding affinities of the perturbed complexes. This is correlated with altered DNA cleaving capabilities. Additionally, altering the binding of the axial primary amine significantly affects the iron coordination sphere as evidenced by reduced π-back-bonding interactions specifically with the pyrimidine ligand. This pyrimidine π-back-bonding appears to play a key role in mediating the electron density localized on the ferrous center, which contributes to the unique oxygen chemistry and reactivity exhibited by Fe11BLM relative to other non-heme iron sites. Oxygen binding to derivatives in which the β-aminoalanine fragment has been removed leads to a high-spin ferric complex and no observed DNA strand scission, in contrast to the long-lived low-spin activated BLM intermediate that precedes DNA degradation.

Original languageEnglish (US)
Pages (from-to)1249-1259
Number of pages11
JournalJournal of the American Chemical Society
Volume120
Issue number6
DOIs
StatePublished - Feb 18 1998
Externally publishedYes

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Bleomycin
Ligation
Catalytic Domain
DNA
Metals
Ligands
Circular Dichroism
Derivatives
Amines
Iron
Oxygen
Circular dichroism spectroscopy
Azides
Dichroism
Mannose
Amides
Sugars
Light absorption
Electronic structure
Carrier concentration

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Spectroscopic investigation of the metal ligation and reactivity of the ferrous active sites of bleomycin and bleomycin derivatives. / Loeb, Kelly E.; Zaleski, Jeffrey M.; Hess, Cynthia D.; Hecht, Sidney; Solomon, Edward I.

In: Journal of the American Chemical Society, Vol. 120, No. 6, 18.02.1998, p. 1249-1259.

Research output: Contribution to journalArticle

Loeb, Kelly E. ; Zaleski, Jeffrey M. ; Hess, Cynthia D. ; Hecht, Sidney ; Solomon, Edward I. / Spectroscopic investigation of the metal ligation and reactivity of the ferrous active sites of bleomycin and bleomycin derivatives. In: Journal of the American Chemical Society. 1998 ; Vol. 120, No. 6. pp. 1249-1259.
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