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Cercosporin-Photocatalyzed [4+1]- and [4+2]-Annulations of Azoalkenes Under Mild Conditions
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Cyclo[n]pyrroles: size and site-specific binding to G-quadruplexes
Erin Shammel Baker1, Jeong Tae Lee, Jonathan L Sessler
1Department of Chemistry and Biochemistry, University of California, Santa Barbara, 93106-9510, USA.
Journal of the American Chemical Society
|February 24, 2006
Summary
Diprotonated cyclo[n]pyrroles bind to human telomeric sequences. Smaller cyclo[n]pyrroles bind more strongly, with external stacking as the dominant mode, suggesting potential for anticancer drug design.
Area of Science:
- Medicinal Chemistry
- Biophysical Chemistry
- Drug Design
Background:
- Stabilizing G-quadruplex structures is a key strategy for anticancer drug development.
- Telomestatin, a natural product, stabilizes G-quadruplexes and inhibits telomerase.
- Cyclo[n]pyrroles are expanded porphyrin analogues structurally similar to telomestatin.
Purpose of the Study:
- To investigate the potential of diprotonated cyclo[n]pyrroles as G-quadruplex stabilizers.
- To determine the binding affinity and mode of cyclo[n]pyrroles with the human telomere repeat sequence.
Main Methods:
- Utilized nano-electrospray ionization mass spectrometry (Nano-ESI-MS) to assess binding.
- Employed ion mobility spectrometry to measure collision cross-sections of complexes.
- Performed molecular dynamics calculations to rationalize experimental observations.
Main Results:
- Smaller cyclo[n]pyrroles exhibited stronger binding to the d(T(2)AG(3))(4) sequence.
- Cyclo[6]pyrrole showed enhanced binding compared to octaethylporphyrin due to its charge.
- Ion mobility data indicated external stacking as the predominant binding mode.
Conclusions:
- Diprotonated cyclo[n]pyrroles interact with G-quadruplexes primarily through external stacking.
- Binding strength is influenced by the size and charge of the cyclo[n]pyrrole molecules.
- These findings support the potential of cyclo[n]pyrroles in anticancer drug design targeting telomerase.
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