Selective abstraction of sup 2 H from C-5 prime of thymidylate in an oligodeoxynucleotide by the radical center at C-6 of the diradical species of neocarzinostatin: Chemical evidence for the structure of the activated drug-DNA complex

Journal Article · Mon Apr 15 04:00:00 EDT 1991 · Proceedings of the National Academy of Sciences of the United States of America; (United States)

DOI:https://doi.org/10.1073/pnas.88.8.3047· OSTI ID:6099860

Meschwitz, S M; Goldberg, I H ^[1]

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1. Harvard Medical School, Boston, MA (United States)

Use has been made of the mechanism of DNA deoxyribose damage by the ene-diyne-containing chromophore of the antitumor antibiotic neocarzinostatin to provide chemical evidence fro the structure of the activated drug-DNA complex. Radical centers at C-2 and C-6 of the diradical form of the glutathione-activated chromophore abstract hydrogen atoms from C-1{prime} of the C residue and C-5{prime} of the T residue in atoms from C-1{prime} of the C residue and C-5{prime} of the T residue in AGC{center dot}GCT to generate a bistranded lesion consisting of an abasic site at C and a strand break at T. This laboratory has proposed a molecular model for the drug-DNA interaction in which the naphthoate moiety of the chromophore intercalates between A{center dot}T and G{center dot}C, placing the diradical core in the minor groove, so that the radical centers at C-6 and C-2 are close to C-5{prime} of T and C-1{prime} of C, respectively. To determine which radical center abstracts one of the hydrogen atoms from C-5{prime}, the self-complementary oligodeoxynucleotide GCAGCGCTGC was synthesized with {sup 2}H at both 5{prime} positions of the T residue and treated with glutathione-activated chromophore. Since direct strand breakage at the T residue exceeds (44% more) abasic site formation at the C residue, other models of drug-DNA interaction leading to only single-strand breaks are also considered.

• OSTI ID: 6099860
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America; (United States), Journal Name: Proceedings of the National Academy of Sciences of the United States of America; (United States) Vol. 88:8; ISSN PNASA; ISSN 0027-8424
• Country of Publication: United States
• Language: English

Related Subjects

550601* -- Medicine-- Unsealed Radionuclides in Diagnostics
62 RADIOLOGY AND NUCLEAR MEDICINE
ANTI-INFECTIVE AGENTS
ANTIBIOTICS
ANTINEOPLASTIC DRUGS
BARYONS
BIOLOGICAL MODELS
DEUTERIUM COMPOUNDS
DRUGS
ELEMENTARY PARTICLES
FERMIONS
HADRONS
HYDROGEN COMPOUNDS
ISOTOPE EFFECTS
MAGNETIC RESONANCE
NEOCARCINOSTATIN
NUCLEAR MAGNETIC RESONANCE
NUCLEIC ACIDS
NUCLEONS
NUCLEOTIDES
OLIGONUCLEOTIDES
ORGANIC COMPOUNDS
PROTONS
RADIOMIMETIC DRUGS
RESONANCE
STRAND BREAKS
THYMIDYLIC ACID