DNA sequence and structure recognition by Fe(II)[center dot]bleomycin

Miscellaneous · Fri Jan 01 00:00:00 EST 1993

OSTI ID:6964984

Kane, S A

The bleomycins (BLMs) are a family of clinically-important antitumor antibiotics whose chemotherapeutic effects are believed to be expressed at the level of DNA degradation. Bleomycin-mediated DNA strand scission is sequence-selective, resulting in cleavage predominantly at [sup 5[prime]]GC[sup 3[prime]] and [sup 5[prime]]GT[sup 3[prime]] sequences. Several structurally-modified bithiazole derivatives equipped with appropriate DNA cleaving moieties have employed to investigate the role of the bithiazole ring system in bleomycin's sequence-selective recognition of DNA. The DNA cleaving moieties included Fe(II) [center dot] EDTA and chelated Co(II). Fe(II) [center dot] EDTA bithiazoles were shown to bind to DNA and mediate DNA strand scission in a sequence-neutral fashion. The Co(II) [center dot] bithiazole A[sub 2] complex induced alkali-labile lesions on duplex DNA; subsequent base treatment resulted in guanine-specific DNA strand scission. DNA damage induced by the CO(II) [center dot] bithiazole A[sub 2] complex was oxygen-dependent, although insensitive to inhibitors of activated forms of oxygen. A mechanistic study of DNA strand scission mediated by the Co(II) [center dot] bithiazole A[sub 2] complex resulted form preferential reactivity at guanine sites, as opposed to a guanine binding selectivity of the bithiazole. The ability of a DNA triple helix to serve as a substrate for Fe(II) [center dot] BLM for the 5[prime]-junction appeared to derive from recognition of a minor groove shape within this sequence, as opposed to intercalation at the junction. This was supported by the observation that Fe(II) [center dot] phleomycin, which is structurally unable to intercalate into DNA, exhibited the same selectivity of triplex cleavage as Fe(II) [center dot] BLM. Cleavage of the DNA triplex could be carried out in the presence of 5 mM Mg(II), suggesting the potential therapeutic relevance of this nucleic acid target for Fe(II) [center dot] BLM.

• Research Organization: Virginia Univ., Charlottesville, VA (United States)
• OSTI ID: 6964984
• Resource Relation: Other Information: Thesis (Ph.D.)
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
37 INORGANIC
ORGANIC
PHYSICAL AND ANALYTICAL CHEMISTRY
BLEOMYCIN
BIOCHEMISTRY
DNA
DNA SEQUENCING
PATTERN RECOGNITION
COBALT COMPLEXES
IRON COMPLEXES
STRUCTURAL CHEMICAL ANALYSIS
ANTI-INFECTIVE AGENTS
ANTIBIOTICS
ANTIMITOTIC DRUGS
ANTINEOPLASTIC DRUGS
CHEMISTRY
COMPLEXES
DRUGS
NUCLEIC ACIDS
ORGANIC COMPOUNDS
TRANSITION ELEMENT COMPLEXES
550400* - Genetics
550200 - Biochemistry
400201 - Chemical & Physicochemical Properties