title: Wittig reaction (with ethylidene triphenylphosphorane) of oxo-hydroxy derivatives of 5β-cholanic acid: Hydrophobicity, haemolytic potential and capacity of derived ethylidene derivatives for solubilisation of cholesterol.
abstract: Bile acid salts are biosurfactants which form mixed micelles with phospholipids in vertebrates. These mixed micelles are suitable for solubilisation of cholesterol. For therapeutic purposes some bile acid salts as sodium ursocholate are used. However, bile acid anions possess low capacity for solubilisation of cholesterol. Thus, synthesis of more hydrophobic and less membranotoxic bile acid derivatives is of the great interest. In this paper Wittig reaction between ethylidene triphenylphosphorane and different bile acids oxo derivatives is examined. Wittig reaction of bile acids has not been studied much. C12 oxo group is inert in this reaction. If Wittig reaction happens on C7 oxo group stereospecifically E ethylidene stereoisomer is obtained, while the same reaction on C3 oxo group leads to more reactive not sterospecific product. In this paper stereochemical course of investigated Wittig reactions is thoroughly analysed. Hydrophobicity of derived products is determined over the temperature (T) dependence on retention coefficients (k) in reversed phase high resolution chromatography. Using method of principle components on k=f(T) matrix it is found that values of first principle components best describe hydrophobicity of analysed bile acids, while the second principal component is responsible for their hydrophilicity. By in silico molecular descriptors: valence connectivity index of order 3 (X3v) and packing density index (PDI), linear regression equations are obtained that can be used to predict hydrophobicity (over retention coefficient) of bile acids that belong to set of more congeneric groups. Membranotoxicity is determined by haemolytic potential. Monoethylidene derivatives of bile acids (in the form of anions) have lower membranotoxicity than deoxycholic acids anion. Sodium salt of deoxycholic acid 7-ethylidene derivative has 11% greater capacity for solubilisation of cholesterol monohydrate than sodium salt of deoxycholic acid.
authors.affiliation: Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Hajduk Veljka 3, 21000 Novi Sad, Serbia. Electronic address: mihaljp@uns.ac.rs.
authors.forename: Mihalj
authors.initials: M
authors.lastname: Poša
authors.affiliation: Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg D. Obradovića 3, 21000 Novi Sad, Serbia.
authors.forename: Srđan
authors.initials: S
authors.lastname: Bjedov
authors.affiliation: Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Hajduk Veljka 3, 21000 Novi Sad, Serbia.
authors.forename: Ana
authors.initials: A
authors.lastname: Sebenji
authors.affiliation: Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg D. Obradovića 3, 21000 Novi Sad, Serbia.
authors.forename: Marija
authors.initials: M
authors.lastname: Sakač
mesh_terms: D002784:Cholesterol / Q000737:chemistry*; D002793:Cholic Acids / Q000737:chemistry*; D006461:Hemolysis / Q000187:drug effects*; D057927:Hydrophobic and Hydrophilic Interactions; D008968:Molecular Conformation; D009943:Organophosphorus Compounds / Q000737:chemistry*; D012995:Solubility / Q000187:drug effects; D013696:Temperature
chemical_list: D002793:Cholic Acids; D009943:Organophosphorus Compounds; D002784:Cholesterol; C007036:cholanic acid
keywords: Bile acids; Haemolitic potential; Hydrophobicity; Principle component method; Solubilisation of cholesterol; Wittig reaction