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Sequence-selective, pH-dependent binding to DNA of benzophenanthridine alkaloids.
N P Bajaj1, M J McLean, M J Waring
1Department of Pharmacology, University of Cambridge Medical School, UK.
Journal of Molecular Recognition : JMR
|February 1, 1990
Summary
Benzophenanthridine alkaloids bind DNA at mixed nucleotide sequences, similar to ethidium bromide. Their DNA binding is enhanced at acidic pH, suggesting a pH-dependent intercalation mechanism.
Area of Science:
- Biochemistry
- Molecular Biology
- Medicinal Chemistry
Background:
- Benzophenanthridine alkaloids are a class of compounds with potential biological activities.
- Understanding their DNA binding properties is crucial for elucidating their mechanisms of action.
Purpose of the Study:
- To analyze the sequence selectivity of DNA binding for three benzophenanthridine alkaloids.
- To compare their binding behavior with ethidium bromide, a known DNA intercalator.
- To investigate the influence of pH on benzophenanthridine-DNA interactions.
Main Methods:
- DNase I footprinting was employed to map the DNA binding sites of the alkaloids.
- Comparative analysis with ethidium bromide binding was performed.
- Experiments were conducted across a range of pH conditions.
Main Results:
- Benzophenanthridines exhibit sequence selectivity, preferentially binding to mixed nucleotide sequences, particularly those with alternating purines and pyrimidines.
- A notable lack of binding was observed at repetitive (AT)n sequences (n ≥ 3).
- DNA binding affinity was significantly enhanced at pH below 7.0, indicating pH-dependent interactions.
Conclusions:
- Benzophenanthridine alkaloids display distinct DNA sequence preferences.
- The pH-dependent binding suggests that the protonation state of the alkaloids influences their interaction with DNA.
- Lowering the pH favors the intercalating species of benzophenanthridines, enhancing their DNA binding efficacy.