ArticleScientific reports2021
Improvement in aqueous solubility of achiral symmetric cyclofenil by modification to a chiral asymmetric analog.
Article in Scientific reports, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Hit-to-Lead Optimization of Energy-Coupling Factor (ECF) Transporter Inhibitors as Novel Antibiotic.Journal of medicinal chemistry · 2026Article
- Development of Prediction Capabilities for High-Throughput Screening of Physiochemical Properties by Biomimetic Chromatography.Molecules (Basel, Switzerland) · 2025Review
- Challenges of Aufheben to Promote Druglikeness: Chemical Modification Strategies to Improve Aqueous Solubility and Permeability.Journal of medicinal chemistry · 2025Review
- Characterization of covalent inhibitors that disrupt the interaction between the tandem SH2 domains of SYK and FCER1G phospho-ITAM.PloS one · 2024Article
- Characterization of covalent inhibitors that disrupt the interaction between the tandem SH2 domains of SYK and FCER1G phospho-ITAM.bioRxiv : the preprint server for biology · 2023Article
- Current Techniques of Water Solubility Improvement for Antioxidant Compounds and Their Correlation with Its Activity: Molecular Pharmaceutics.Antioxidants (Basel, Switzerland) · 2023Review
- Evaluation of 3-Borono-l-Phenylalanine as a Water-Soluble Boron Neutron Capture Therapy Agent.Pharmaceutics · 2022Article
Corrections and comments
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Authors and funding
7 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Decreasing the partition coefficient (LogP) by the introduction of a hydrophilic group is the conventional approach for improving the aqueous solubility of drug candidates, but is not always effective. Since melting point is related to aqueous solubility, we and other groups have developed alternative strategies to improve solubility by means of chemical modification to weaken intermolecular interaction in the solid state, thereby lowering the melting point and increasing the solubility. Here, we show that converting the symmetrical molecular structure of the clinically used estrogen receptor (ER) antagonist cyclofenil (1) into asymmetrical form by introducing an alkyl group enhances the aqueous solubility. Among the synthesized analogs, the chiral methylated analog (R)-4c shows the highest solubility, being 3.6-fold more soluble than 1 even though its hydrophobicity is increased by the methylation. Furthermore, (R)-4c also showed higher membrane permeability than 1, while retaining a comparable metabolic rate, and equivalent biological activity of the active forms (R)-13a to 2. Further validation of this strategy using lead compounds having symmetric structures is expected.
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Registered trials
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