Synthesis of New Water-Soluble Cholesterol Derivatives

Abstract

Water-soluble cholesterol derivatives for studies investigating the role of cholesterol in mammalian cells under physiological conditions are rare. Therefore, efficient syntheses for new cholesterol derivatives with enhanced water solubility have been developed. Either substitution at C(3)-OH of cholesterol with ethylene glycols or reductive amination at the keto group of pregnenolone yielded steroids with significantly increased water solubility. The solubility of the cholesterol derivatives in water was determined by ¹H NMR spectroscopy in D₂O with 2,2-dimethyl-2-silapentane-5-sulfonate (DSS) as reference to be 1 to 6 mg/mL at room temperature. The comparison of resonance signal line width in water and chloroform solution showed little aggregation for compounds 4 and 5, while broader resonance signals indicate micelle formation for compound 9.

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Keywords:

• Cholesterol
• ethylene glycol
• reductive amination
• steroid
• water-soluble

Notes

Notes. I_DSS,theoret. = 9, I_{Chol.,theoret.} = 3.

^a Spectra of saturated solutions of 4 did not show any aggregation effects. Therefore, water solubility of 4 was calculated from those integrals.

^b At high concentrations, 5 was found to form aggregates and hence a saturated solution of 5 was diluted (1:12.5) to obtain spectra from which water solubility of single molecules could be determined.

^c Aggregates of 9 could not be disrupted by dilution (1:5); consequently, maximum concentration of aggregates of 9 in aqueous solution was determined from a saturated solution.

^d Because of strong line broadening in the steroid range of the obtained spectra for 9, the overall integral for the ethylene glycol chain was used for calculation, because this signal group was found to be hardly affected by aggregation.

^e No cholesterol-derived signals were detected in spectra obtained for saturated solution of cholesterol.

^f Literature-derived value determined at 30 °C.

^g Not investigated.