Sites in the diyne-ene bicyclic core of neocarzinostatin chromophore responsible for hydrogen abstraction from DNA

Journal Article · Tue Oct 18 04:00:00 EDT 1988 · Biochemistry; (USA)

DOI:https://doi.org/10.1021/bi00421a020· OSTI ID:6831828

Ching, Derhang; Goldberg, I H ^[1]; Zeng, Chenhui; Costello, C E ^[2]

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1. Harvard Medical School, Boston, MA (USA)
2. Massachusetts Institute of Technology, Cambridge, MA (USA)

The antitumor antibiotic neocarzinostatin exhibits its main drug action by abstracting hydrogen from DNA deoxyribose with consequent strand breakage or related lesions. All biological activities of the drug derive solely from a nonprotein chromophoric substance (NCS-chrom) consisting of a novel epoxy-bicyclo-diyne-ene system. Thiol or sodium borohydride activates NCS-chrom into a labile, reactive species that induces DNA damage but causes inactivation of the drug in the absence of the target DNA. Since three deuterium atoms can be incorporated into the drug by treatment with sodium borodeuteride without DNA, adding an unlabeled DNA under parallel conditions permitted the ready identification of the activated NCS-chrom product that abstracted hydrogen from the DNA. Not only does the activated NCS-chrom product have the same structure as the inactivated drug without DNA, but two of the incorporated deuterium atoms have been substituted by hydrogen. With the aid of NMR spectrometry, the two replaced hydrogen atoms are found to be incorporated into the C-2 and C-6 positions of the bicyclo-diyne-ene ring of NCS-chrom and are derived neither from borodeuteride nor from the hydroxyl functions of the solvents. In accord with current proposals, the two hydrogens incorporated into the drug may come from closely opposed sites on the complementary strands of the DNA at which the drug is bound. These findings are consistent with a diradical mechanism in which carbon-centered radicals at C-2 and C-6 of the activated drug result in abstraction of hydrogen atoms either from the deoxyribose moiety of DNA or, in the absence of DNA, from some other source, but not from the hydrogen attached to the sulfur of thiols under the conditions described.

• OSTI ID: 6831828
• Journal Information: Biochemistry; (USA), Journal Name: Biochemistry; (USA) Vol. 27:21; ISSN 0006-2960; ISSN BICHA
• Country of Publication: United States
• Language: English

Related Subjects

550201 -- Biochemistry-- Tracer Techniques
560300* -- Chemicals Metabolism & Toxicology
59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ALDEHYDES
ALKALI METAL COMPOUNDS
ANTI-INFECTIVE AGENTS
ANTIBIOTICS
ANTINEOPLASTIC DRUGS
BOROHYDRIDES
BORON COMPOUNDS
CARBOHYDRATES
CHEMICAL REACTIONS
CHROMATOGRAPHY
CROSS-LINKING
DEOXYRIBOSE
DEUTERIDES
DEUTERIUM COMPOUNDS
DNA
DRUGS
HYDROGEN COMPOUNDS
LIQUID COLUMN CHROMATOGRAPHY
MAGNETIC RESONANCE
MASS SPECTROSCOPY
MONOSACCHARIDES
NEOCARCINOSTATIN
NMR SPECTRA
NUCLEAR MAGNETIC RESONANCE
NUCLEIC ACIDS
ORGANIC COMPOUNDS
PENTOSES
POLYMERIZATION
RADIOMIMETIC DRUGS
RESONANCE
SACCHARIDES
SEPARATION PROCESSES
SODIUM COMPOUNDS
SPECTRA
SPECTROSCOPY
STRAND BREAKS
TRITIUM COMPOUNDS