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

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...

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Autores principales:	Junki Morimoto, Kazunori Miyamoto, Yuki Ichikawa, Masanobu Uchiyama, Makoto Makishima, Yuichi Hashimoto, Minoru Ishikawa
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6da4c61e46e044feab315317688174ce
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spelling	oai:doaj.org-article:6da4c61e46e044feab315317688174ce2021-12-02T17:41:32ZImprovement in aqueous solubility of achiral symmetric cyclofenil by modification to a chiral asymmetric analog10.1038/s41598-021-92028-y2045-2322https://doaj.org/article/6da4c61e46e044feab315317688174ce2021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-92028-yhttps://doaj.org/toc/2045-2322Abstract 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.Junki MorimotoKazunori MiyamotoYuki IchikawaMasanobu UchiyamaMakoto MakishimaYuichi HashimotoMinoru IshikawaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Junki Morimoto Kazunori Miyamoto Yuki Ichikawa Masanobu Uchiyama Makoto Makishima Yuichi Hashimoto Minoru Ishikawa Improvement in aqueous solubility of achiral symmetric cyclofenil by modification to a chiral asymmetric analog
description	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.
format	article
author	Junki Morimoto Kazunori Miyamoto Yuki Ichikawa Masanobu Uchiyama Makoto Makishima Yuichi Hashimoto Minoru Ishikawa
author_facet	Junki Morimoto Kazunori Miyamoto Yuki Ichikawa Masanobu Uchiyama Makoto Makishima Yuichi Hashimoto Minoru Ishikawa
author_sort	Junki Morimoto
title	Improvement in aqueous solubility of achiral symmetric cyclofenil by modification to a chiral asymmetric analog
title_short	Improvement in aqueous solubility of achiral symmetric cyclofenil by modification to a chiral asymmetric analog
title_full	Improvement in aqueous solubility of achiral symmetric cyclofenil by modification to a chiral asymmetric analog
title_fullStr	Improvement in aqueous solubility of achiral symmetric cyclofenil by modification to a chiral asymmetric analog
title_full_unstemmed	Improvement in aqueous solubility of achiral symmetric cyclofenil by modification to a chiral asymmetric analog
title_sort	improvement in aqueous solubility of achiral symmetric cyclofenil by modification to a chiral asymmetric analog
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/6da4c61e46e044feab315317688174ce
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Improvement in aqueous solubility of achiral symmetric cyclofenil by modification to a chiral asymmetric analog

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