Structure-Property Relationships in Sodium Muricholate Derivative (Bile Salts) Micellization: The Effect of Conformation of Steroid Skeleton on Hydrophobicity and Micelle Formation-Pattern Recognition and Potential Membranoprotective Properties

Mol Pharm. 2017 Oct 2;14(10):3343-3355. doi: 10.1021/acs.molpharmaceut.7b00375. Epub 2017 Sep 13.

Abstract

It is known that β-muricholic acid anions prevent membrane toxicity of hydrophobic bile acids, which are being used in therapy for solubilization of the cholesterol type bile stone. Better knowledge of these derivative micelles is very important for understanding their physiological and pharmacological effects. β-Axial (a) oriented hydroxyl group from the steroid skeleton decreases the hydrophobic surface of the convex side of the steroid skeleton. Therefore, the critical micellization concentration (CMC) for steroid surfactants with β-a-OH group should increase, but in the case of OH groups of different orientations forming H-bonds in the hydrophobic phase of the micelle, it has the opposite effect; the CMC decreses, and aggregation is more favored. The set of muricholic acids (MCs) is composed by α-MC, β-MC, γ-MC, and ω-MC, where α-MC and β-MC have β-axial-OH groups. The aggregation numbers (n) are determined using the Moroi-Matsuoka-Sugioka thermodynamic method. CMC, enthalpy of demicellization, and ΔCp are determined by isothermal titration calorimetry (ITC). This report pioneers in the study of MC derivatives micellization. Micelles of β-MC and γ-MC belong to the linear congeneric group (LCG) and their micelles above 85 mM have constant aggregation numbers n = 4-5. Micelles of α-MC and ω-MC are outliers in relation to the LCG, their aggregation number constantly increases; at 85 mM n = 6.8 (α-MC) and 6.5 (ω-MC). In micelles of derivatives β-MC and γ-MC, there is a low probability for the existence of hydrogen bonds. A micelle of α-MC probably has hydrogen bonds in its hydrophobic domain.

Keywords: aggregation number; conformational analysis; hydrophobic drug; hydrophobic linear congeneric groups; steroid skeleton.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bile Acids and Salts / chemistry*
  • Bile Acids and Salts / therapeutic use
  • Bile Acids and Salts / toxicity
  • Calorimetry
  • Cell Membrane / drug effects*
  • Chemistry, Pharmaceutical
  • Cholelithiasis / therapy
  • Cholic Acids / chemistry
  • Gastrointestinal Agents / chemistry*
  • Gastrointestinal Agents / therapeutic use
  • Gastrointestinal Agents / toxicity
  • Humans
  • Hydrogen Bonding
  • Hydrophobic and Hydrophilic Interactions
  • Micelles*
  • Molecular Conformation
  • Sodium / chemistry
  • Surface-Active Agents
  • Thermodynamics

Substances

  • Bile Acids and Salts
  • Cholic Acids
  • Gastrointestinal Agents
  • Micelles
  • Surface-Active Agents
  • muricholic acid
  • Sodium