Characterization and Solubilization of Pyrrole鈥揑midazole Polyamide Aggregates

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• 作者：Amanda E. Hargrove ; Jevgenij A. Raskatov ; Jordan L. Meier ; David C. Montgomery ; Peter B. Dervan
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：June 14, 2012
• 年：2012
• 卷：55
• 期：11
• 页码：5425-5432
• 全文大小：404K
• 年卷期：v.55,no.11(June 14, 2012)
• ISSN：1520-4804

文摘

To optimize the biological activity of pyrrole鈥搃midazole 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鈥?00 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-尾-cyclodextrin (Hp尾CD). In mice, the use of Hp尾CD 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.