A bifunctional dimethylsulfoxide substitute enhances the aqueous solubility of small organic molecules

Abstract

An oxetane-substituted sulfoxide has demonstrated potential as a dimethylsulfoxide substitute for enhancing the dissolution of organic compounds with poor aqueous solubilities. This sulfoxide may find utility in applications of library storage and biological assays. For the model compounds studied, significant solubility enhancements were observed using the sulfoxide as a cosolvent in aqueous media. Brine shrimp, breast cancer (MDA-MB-231), and liver cell line (HepG2) toxicity data for the new additive are also presented, in addition to comparative IC(50) values for a series of PKD1 inhibitors.

Fig. 1.

Structures of sulfoxides used for compound storage or aqueous solubility enhancement.

Fig 2.

Synthesis of water-soluble sulfoxide 3.

Fig. 3.

Compounds screened in the aqueous solubility study.

Fig. 4.

Solubility of quinine 8 in aqueous solutions with sulfoxide 3 (△) and DMSO (+) as cosolvents. Each trial was run in duplicate and each point represents the average of the duplicate trials. In the case of sulfoxide 3, the pH ranged from 8.7 (with no additive) to 9.4 (with a 0.25 weight fraction additive). In the case of DMSO, the pH ranged from 8.9 (with no additive) to 9.5 (with a 0.25 weight fraction additive). DMSO, dimethylsulfoxide.

Fig. 5.

Solubility of naproxen 9 in aqueous solutions with sulfoxide 3 (△) and DMSO (+) as cosolvents. Each trial was run in duplicate and each point represents the average of the duplicate trials. In the case of sulfoxide 3, the pH ranged from 4.6 (with no additive) to 4.2 (with a 0.25 weight fraction additive). In the case of DMSO, the pH ranged from 4.8 to 4.4.

Fig. 6.

Solubility of carbendazim 10 in aqueous solutions with sulfoxide 3 (△) and DMSO (+) as cosolvents. Each trial was run in duplicate and each point represents the average of the duplicate trials. In the case of sulfoxide 3, the pH ranged from 6.7 (with no additive) to 7.0 (with a 0.15 weight fraction additive). In the case of DMSO, the pH ranged from 6.8 (with no additive) to 7.4 (with a 0.25 weight fraction additive).

Fig. 7.

Solubility of griseofulvin 11 in aqueous solutions with sulfoxide 3 (△) and DMSO (+) as cosolvents. Each trial was run in duplicate and each point represents the average of the duplicate trials. In the case sulfoxide 3, the pH ranged from 6.3 (with no additive) to 6.8 (with a 0.20 weight fraction additive). In the case of DMSO, the pH ranged from 6.3 (with no additive) to 6.8 (with a 0.20 weight fraction additive).

Fig. 8.

Compounds assayed for PKD1 inhibitory activity. The structures have been reported previously.^– PKD1, protein kinase D isoform 1.

Fig. 9.

Plot of PKD1 activity with compound concentrations of 1 μM. Stock solutions were prepared in three different media [DMSO (), NMP (□), and 25% 3/NMP (▪)] at concentrations of 10 mM, and dilutions were performed using the same media. The % PKD1 activity is reported as the mean, and error bars represent SEM (n=3). The % PKD1 activity was determined as previously described.²⁴ NMP, N-methylpyrrolidinone; SEM, standard error of the mean.

Fig. 10.

Plot of PKD1 activity with compound concentrations of 10 μM. Stock solutions were prepared in three different media [DMSO (), NMP (□), and 25% 3/NMP (▪)] at concentrations of 10 mM, and dilutions were performed using the same media. The % PKD1 activity is reported as the mean, and error bars represent SEM (n=3). The % PKD1 activity was determined as previously described.