Potentiometric Determination of Acid Dissociation Constants (p Ka) for an Anticancer Pyrrole-Imidazole Polyamide

Li，Xue; Shi，Zhaofang; Jia，Tiezheng

2022-11-10

10.1021/acsmedchemlett.2c00348

ACS Medicinal Chemistry Letters   Impact Factor & Quartile

1948-5875

1948-5875

To optimize the pharmacological properties of an anticancer pyrrole-imidazole (Py-Im) polyamide (PIP-1), we characterized the acid dissociation constants of PIP-1, three other structurally related hairpin-shaped polyamides, and a cyclic polyamide bearing the same core sequence as PIP-1 via potentiometric titration. The acidities of the carboxylic acid at the C-terminus and the tertiary amine in the triamine linker remained very similar among the polyamides tested, whereas the pKof the N-methylimidazole (Im) moieties varied with the peptide sequence and molecular architecture. A nearly 0.2 pH unit pKshift of terminal Im toward the neutral state compared to internal Im was observed. Furthermore, according to the dissociation constants, a speciation diagram of PIP-1 as a function of pH is presented, which allows an assessment of the net charge and distribution of protonated species in the range of physiological pH.

N-methylimidazole p Ka potentiometric titration protonation profiling Py-Im polyamide

SCI

English

First ; Corresponding

[2022A1515011770] ; [2021B1515120046] ; [2020B121201002]

Pharmacology & Pharmacy

Chemistry, Medicinal

WOS:000877867400001

AMER CHEMICAL SOC

2-s2.0-85141017010

Scopus

Research Center for Chemical Biology and Omics Analysis,Department of Chemistry,Guangdong Provincial Key Laboratory of Catalysis,Southern University of Science and Technology,Shenzhen,1088 Xueyuan Boulevard, Guangdong,518055,China

Li，Xue,Shi，Zhaofang,Jia，Tiezheng. Potentiometric Determination of Acid Dissociation Constants (p Ka) for an Anticancer Pyrrole-Imidazole Polyamide[J]. ACS Medicinal Chemistry Letters,2022,13(11):1739-1744.

Li，Xue,Shi，Zhaofang,&Jia，Tiezheng.(2022).Potentiometric Determination of Acid Dissociation Constants (p Ka) for an Anticancer Pyrrole-Imidazole Polyamide.ACS Medicinal Chemistry Letters,13(11),1739-1744.

Li，Xue,et al."Potentiometric Determination of Acid Dissociation Constants (p Ka) for an Anticancer Pyrrole-Imidazole Polyamide".ACS Medicinal Chemistry Letters 13.11(2022):1739-1744.