Hargrove, Amanda E. and Raskatov, Jevgenij A. and Meier, Jordan L. and Montgomery, David C. and Dervan, Peter B. (2012) Characterization and Solubilization of Pyrrole−Imidazole Polyamide Aggregates. Journal of Medicinal Chemistry, 55 (11). pp. 5425-5432. ISSN 0022-2623 http://resolver.caltech.edu/CaltechAUTHORS:20120716-095438604
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Abstract
To optimize the biological activity of pyrrole–imidazole polyamide DNA-binding molecules, we characterized the aggregation propensity of these compounds through dynamic light scattering and fractional solubility analysis. Nearly all studied polyamides were found to form measurable particles 50–500 nm in size under biologically relevant conditions, while HPLC-based analyses revealed solubility trends in both core sequences and peripheral substituents that did not correlate with overall ionic charge. The solubility of both hairpin and cyclic polyamides was increased upon addition of carbohydrate solubilizing agents, in particular, 2-hydroxypropyl-β-cyclodextrin (HpβCD). In mice, the use of HpβCD allowed for improved injection conditions and subsequent investigations of the availability of polyamides in mouse plasma to human cells. The results of these studies will influence the further design of Py-Im polyamides and facilitate their study in animal models.
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| Additional Information: | © 2012 American Chemical Society. Received: March 20, 2012. Publication Date (Web): May 18, 2012. We thank Dr. Jennifer Keefe (California Institute of Technology) and Sigrid Kuebler (Wyatt Technology Corporation) for assistance with DLS experimentation and data analysis and Dr. Adam Urbach (Trinity University) for helpful discussions. A.E.H. thanks the California Tobacco-Related Disease Research Program (19FT-0105) and the NIH (NRSA number 1F32CA156833) for postdoctoral support. J.A.R. is grateful to the Alexander von Humboldt foundation for the award of a Feodor Lynen postdoctoral fellowship. J.L.M. acknowledges the American Cancer Society for a postdoctoral fellowship (PF-10-015-01-CDD). D.C.M. thanks the National Institutes of Health for a Cellular, Biochemical, and Molecular Sciences Predoctoral Research training grant (5T32GM007616). This work was supported by the Ellison Medical Foundation (AG-SS-2256-09) and NIH grants (GM27681, GM51747). | ||||||||||||||||||
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| Record Number: | CaltechAUTHORS:20120716-095438604 | ||||||||||||||||||
| Persistent URL: | http://resolver.caltech.edu/CaltechAUTHORS:20120716-095438604 | ||||||||||||||||||
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| Official Citation: | Characterization and Solubilization of Pyrrole–Imidazole Polyamide Aggregates Amanda E. Hargrove, Jevgenij A. Raskatov, Jordan L. Meier, David C. Montgomery, and Peter B. Dervan Journal of Medicinal Chemistry 2012 55 (11), 5425-5432 | ||||||||||||||||||
| Usage Policy: | No commercial reproduction, distribution, display or performance rights in this work are provided. | ||||||||||||||||||
| ID Code: | 32460 | ||||||||||||||||||
| Collection: | CaltechAUTHORS | ||||||||||||||||||
| Deposited By: | Ruth Sustaita | ||||||||||||||||||
| Deposited On: | 16 Jul 2012 17:30 | ||||||||||||||||||
| Last Modified: | 26 Dec 2012 15:32 |
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