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Parallel synthesis of H-pin polyamides by alkene metathesis on solid phase
Bogdan Olenyuk1, Cristian Jitianu, Peter B Dervan
1Division of Chemistry and Chemical Engineering, The Beckman Institute, California Institute of Technology, Pasadena, California 91125, USA.
Journal of the American Chemical Society
|April 17, 2003
Summary
Researchers developed H-pin polyamides for DNA binding. An optimal six-methylene bridge length was identified, showing high affinity and specificity, advancing gene regulation studies.
Area of Science:
- Organic Chemistry
- Molecular Biology
- Medicinal Chemistry
Background:
- Polyamides are versatile molecules for DNA recognition.
- H-pin polyamides offer a novel structural motif for DNA binding.
- Developing efficient synthetic routes is crucial for exploring structure-activity relationships.
Purpose of the Study:
- To synthesize a library of H-pin polyamides with varying aliphatic bridge lengths.
- To investigate the impact of linker length on DNA binding affinity and sequence specificity.
- To establish an optimal H-pin polyamide structure for gene regulation applications.
Main Methods:
- Parallel synthesis utilizing ruthenium-catalyzed alkene metathesis on solid phase.
- Preparation of H-pin polyamides with methylene bridge lengths (CH2)n, where n = 4-8.
- DNA binding assays to quantify affinity and sequence specificity.
Main Results:
- A library of H-pin polyamides was successfully synthesized.
- The H-pin polyamide with a six-methylene bridge exhibited the highest DNA binding affinity and selectivity.
- Affinity ranking based on methylene bridge length: n = 6 > 4 > 7 > 5 > 8.
- H-pin polyamides demonstrated competitive affinity and specificity compared to hairpin polyamides.
Conclusions:
- The optimal spacer length for H-pin polyamides in the DNA minor groove is six methylenes.
- The developed metathesis-based synthesis provides a versatile route to H-pin polyamides.
- These findings expand the toolkit of small molecules for gene regulation.
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