Suppression of Problematic Compound Oligomerization by Cosolubilization of Nondetergent Sulfobetaines

• Published in: ChemMedChem Vol. 10; no. 4; pp. 736 - 741
• Main Authors: Mizukoshi, Yumiko, Takeuchi, Koh, Arutaki, Misa, Takizawa, Takeshi, Hanzawa, Hiroyuki, Takahashi, Hideo, Shimada, Ichio
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.04.2015; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Subjects: Anti-Inflammatory Agents, Non-Steroidal - chemistry; Aqueous solutions; Betaine - analogs & derivatives; Betaine - chemistry; Drug Discovery; Equilibrium; Imidazoles - chemistry; Magnetic Resonance Spectroscopy; NMR; NMR spectroscopy; nondetergent sulfobetaines; Nuclear magnetic resonance; oligomerization; Solubility; Solutions; Thiazoles - chemistry; nondetergent sulfobetaines; drug discovery; oligomerization; NMR spectroscopy; artifacts
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201500057

Numerous small organic compounds exist in equilibrium among monomers, soluble oligomers, and insoluble aggregates in aqueous solution. Compound aggregation is a major reason for false positives in drug screening, and even soluble oligomers can interfere with structural and biochemical analyses. However, an efficient way to manage the equilibrium of aggregation‐prone compounds, especially those involved with soluble oligomers, has not been established. In this study, solution NMR spectroscopy was used as a suitable technique to detect compound oligomers in equilibrium, and it was demonstrated that cosolubilization of nondetergent sulfobetaines (NDSBs) can largely suppress compound oligomerization and aggregation by shifting the equilibrium toward the monomers. The rotational correlation time was obtained from the ratio of the selective and nonselective longitudinal NMR relaxation times, which directly and quantitatively reflected the apparent sizes of the compounds in the equilibrium. The rotational correlation time of the aggregation‐prone compound SKF86002 (1 mM) was substantially reduced from 0.31 to 0.23 ns by cosolubilization of 100 mM NDSB195. NDSB cosolubilization allowed us to perform successful structural and biochemical experiments with substantially fewer artifacts, which represents a strategy to directly resolve the problematic oligomerization and aggregation of compounds. Let's disappear together: Solution NMR spectroscopy reveals that cosolubilization of nondetergent sulfobetaines (NDSBs) has the ability to suppress the problematic assembly of aggregation‐prone compounds by shifting the equilibrium among the monomers, oligomers, and aggregates towards the monomers. This substantially reduces the artifacts in the structural and biochemical assays, which is beneficial in structure‐based drug development.