New Class of DNA-Cleaving Agents Based on Trimethylenemethane

Bregant, Therese M.; Groppe, Jay C.; Little, R. Daniel

doi:10.1021/ja00087a074

Cited by 38 publications

(36 citation statements)

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“…The netropsin-diazene was synthesized as described previously (Bregant et al, 1994). The oligomers d(CGCAAAAGGC) and d(GCCTHTGCG) were synthesized and purified as described in Chapter 2.…”

Section: Synthesis Of Ligands Andmentioning

confidence: 99%

“…Recent studies have shown that photolysis of netropsin-diazene in the presence of DNA leads to the formation of single stranded breaks in the phosphodiester backbone of DNA (Bregant et al, 1994), and characterization of the cleavage products to determine the exact site of cleavage is under way. It appears that double strand breaks are more important than single strand lesions with respect to mutagenicity and cytotoxicity.…”

Section: Synthesis Of Ligands Andmentioning

confidence: 99%

“…In principle the reduced reactivity of the delocalized ndiyl may result in decreased overall toxicity (Nicolaou & Dai, 1991). TMM diyls have been shown to cleave DNA (Bregant et al, 1994), and the mechanism of cleavage is currently being studied (R. D. Little, unpublished results). Additionally, TMM diyls can be generated by the thermolysis or photolysis of diazenes (Little et al, 1992;Billera & Little, 1994;Bregant et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

“…TMM diyls have been shown to cleave DNA (Bregant et al, 1994), and the mechanism of cleavage is currently being studied (R. D. Little, unpublished results). Additionally, TMM diyls can be generated by the thermolysis or photolysis of diazenes (Little et al, 1992;Billera & Little, 1994;Bregant et al, 1994). Photoactivation has the added advantage of allowing precise control of the initiation and duration of the cleaving reaction.…”

Section: Introductionmentioning

confidence: 99%

“…• A DNA cleaving agent based on diazene, a TMM diradical precursor, and netropsin was designed and synthesized in the laboratory of Professor R. D. Little (Figure 3-2c) (Bregant et al, 1994). The use of a lexitropsin is a particularly attractive choice because the binding behavior and DNA sequence selectivity of lexitropsins are well-documented, and the minimum length of a lexitropsin binding site is four base pairs.…”

Section: Introductionmentioning

confidence: 99%

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NMR studies of DNA oligomers and their interactions with minor groove binding ligands

Fagan

1996

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Molecules which direct chemistry to a specific DNA sequence could be used as antiviral compounds, diagnostic probes, or molecular biology tools. I studied two ligands in which reactive groups were tethered to a distamycin to increase the sequence specificity 1 of the reactive agent. The DNA cleaving agent netropsin-diazene binds at the predicted DNA site, but the presence of the diazene reduces the affinity and the orientational preference of the ligand compared to distamycin. A tethered ligand containing a 2,3-bis(hydroxymethyl) pyrrole crosslinked to a DNA duplex exhibits many similarities to mitomycin C:DNA complexes. The tether unexpectedly bridges one base pair. These results are important considerations in ligand design, since sometimes ligand binding behavior cannot be predicted from the behavior of the parent molecule.The pairing geometry of cytosine with the highly mutagenic base analog 2-aminopurine has been debated for years. With the use of NMR spectroscopy and selectively 15 N-labeled DNA, the AP«C mispair was found to form a wobble geometry.The structure and stability of this base mispair depend upon the local base sequence.Approved: ., ( -,"_,,,

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“…The netropsin-diazene was synthesized as described previously (Bregant et al, 1994). The oligomers d(CGCAAAAGGC) and d(GCCTHTGCG) were synthesized and purified as described in Chapter 2.…”

Section: Synthesis Of Ligands Andmentioning

confidence: 99%

Section: Synthesis Of Ligands Andmentioning

confidence: 99%