Improvement in aqueous solubility of achiral symmetric cyclofenil by modification to a chiral asymmetric analog

• Published in: Scientific reports Vol. 11; no. 1; p. 12697
• Main Authors: Morimoto, Junki, Miyamoto, Kazunori, Ichikawa, Yuki, Uchiyama, Masanobu, Makishima, Makoto, Hashimoto, Yuichi, Ishikawa, Minoru
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.06.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/154/309/2419; 631/92/2783; Biological activity; Carbon; Chemical modification; Design; Drug development; Estrogen receptors; Estrogens; Humanities and Social Sciences; Hydrophobicity; Melting; Melting point; Membrane permeability; Metabolic rate; Methylation; Molecular structure; multidisciplinary; Permeability; Pharmaceuticals; Science; Science (multidisciplinary); Solubility; Symmetry
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-92028-y

Decreasing the partition coefficient (Log P ) 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.