DNA triple-helix specific intercalators as antigene enhancers: unfused aromatic cations.
Triple-helical structures involving the interaction of an oligonucleotide third strand with a duplex nucleic acid sequence have recently gained attention as a therapeutic strategy in the "antigene" approach [cf. Helene, C. (1991) Eur. J. Cancer 27, 1466-1471]. This method utilizes the triple helix formed from the cellular duplex and an added third strand to directly regulate the activity of a selected gene. The limited stability of nucleic acid triple-helical interactions, particularly if the third strand has backbone modifications such as methylphosphonate or phosphorothioate substitutions, is a limiting condition for the use of this approach. We have designed and synthesized compounds, on the basis of the following three criteria, that we feel should provide selective interactions and significant stabilization of triplexes: appropriate aromatic surface area for stacking with triplex bases in an intercalation complex, positive charge, and limited torsional freedom in the aromatic system to match the propeller twist of the triple-base interactions in the triplex. A series of quinoline derivatives with an alkylamine side chain at the 4-position and with different aryl substituents at the 2-position has been synthesized as our first compounds. A 2-naphthyl derivative provides significant and selective stabilization of the triplex. In a 0.2 M NaCl buffer, the naphthyl derivative increased the Tm for the triplex (triplex to duplex and third strand transition) by approximately 30 degrees C more than the Tm increase for the duplex (duplex to single strands transition). Spectral changes and energy-transfer results indicate that the naphthyl compound and related derivatives bind to the triplex by intercalation.(ABSTRACT TRUNCATED AT 250 WORDS)
Wilson
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Department of Chemistry and Laboratory for Chemical and Biological Sciences, Georgia State University, Atlanta 30303.
Tanious
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Mizan
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Yao
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Kiselyov
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Zon
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Strekowski
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D004247:DNA / Q000737:chemistry*; D006860:Hydrogen Bonding; D007202:Indicators and Reagents; D007364:Intercalating Agents / Q000737:chemistry*; D008958:Models, Molecular; D008961:Models, Structural; D009690:Nucleic Acid Conformation; D009691:Nucleic Acid Denaturation; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis / Q000737:chemistry*; D063065:Organophosphonates; D063086:Organothiophosphates; D013816:Thermodynamics
D007202:Indicators and Reagents; D007364:Intercalating Agents; D009838:Oligodeoxyribonucleotides; D063065:Organophosphonates; D063086:Organothiophosphates; C027903:oligo (dT); C030570:oligodeoxyadenylic acid; D004247:DNA