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

Thesis/Dissertation · Fri Jan 01 04:00:00 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
• Country of Publication: United States
• Language: English

Related Subjects

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