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Alternative Title
Study on the Protonation States of Pyrrole-Imidazole Polyamides
Name pinyin
LI Xue
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070302 分析化学
Subject category of dissertation
07 理学
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Other Abstract

Pyrrole-imidazole polyamides are a class of small molecules that penetrate cell membrane, access cell nucleus, and bind to the minor groove of DNA via non-covalent hydrogen bonds in high affinities and sequence specificities. They possess various biological functions, such as inhibiting gene transcription and manipulating gene expression. As shown in recent studies, pyrrole-imidazole polyamides which target androgen reaction element are effective in the treatment of metastatic castration-resistant prostate cancer in Enzalutamide-resistant cell lines and xenograft animal models. A pyrrole-imidazole polyamide molecule, which targets promoter of Androgen Receptor (AR)-initiated signaling pathway of prostate cancer, has been developed as a drug candidate, and entered phase I of clinical research.

Over ninety percent of drugs are weak acids or bases. The protonation degree of weak acids/bases determinates the proportion of ionic and molecular species, which are directly related to the solubility and lipid distribution of drugs. Furthermore, the protonation degree can influence the absorption, distribution, metabolism and elimination of drugs in vivo. Pyrrole-imidazole polyamides contain several ionizable functional groups, including carboxylic acid, tertiary amine and N-methylimidazole. The protonation degree of polyamides can be reflected by acid dissociation constants and the pH values in solution. Therefore, the accurate measurement of the acidity dissociation constant of pyrrole-imidazole polyamides, especially the N-methylimidazole subgroup, is of great value to reveal the ionic forms and protonation degree in the physiological environment.

There are many methods to determinate the acid dissociation constants, such as potentiometric titration, UV-Visible spectrophotometry titration, nuclear magnetic resonance, capillary electrophoresis, among others. In this study, an easy-operating potentiometric titration was used to determine the acid dissociation constants of polyamides with high accuracy and reproducibility. In addition, the impact of peptide sequence and molecular shape on the dissociation constants of N-methylimidazole moieties was evaluated. Then by calculating the function of acid dissociation constant and pH, the mutual conversion between species (cationic, neutral and anionic) at different pH environments were presented. Moreover, the species distribution and proportion of polyamides in the process of penetrating cell membrane and accessing nucleus were summarized. This study provides a guidance of pharmacokinetic properties and delivery of polyamides, paving the road for biological applications of this class of powerful molecules

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References List

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李雪. 吡咯-咪唑聚酰胺的质子化状态研究[D]. 深圳. 南方科技大学,2022.
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