Click chemistry as a method for the synthesis of steroid bioconjugates of bile acids derivatives and sterols

Abstract

Six steroid conjugates of bile acids and sterol derivatives have been synthesized using the click chemistry method. The azide-alkyne Huisgen cycloaddition of the propionyl ester of lithocholic, deoxycholic and cholic acid with azide derivatives of cholesterol and cholestanol gave new bile acid–sterol conjugates linked with a 1,2,3-triazole ring. Previously, sterols were converted to bromoacetate substituted derivatives by reaction with bromoacetic acid bromide in anhydrous dichloromethane. These compounds were then converted to azide derivatives using sodium azide. The propiolic esters of lithocholic, deoxycholic and cholic acids were obtained by reaction with propiolic acid in the presence of p-toluenesulfonic acid. Additionally, two of these steroids: methyl 3α-propynoyloxy-12α-acetoxy-5β-cholane-24-oate and methyl 3α-propynoyloxy-7 α,12α-diacetoxy-5β-cholane-24-oate were also obtained and characterized for the first time. All conjugates were obtained in good yields using an efficient synthesis method. The structures of all conjugates and the four substrates were confirmed by spectral (1H- and 13C NMR, FT-IR) analysis, mass spectrometry (ESI-MS), and PM5 semiempirical methods. The pharmacotherapeutic potential of the synthesized compounds was estimated based on the in silico Prediction of Activity Spectra for Substances (PASS) method. The cytotoxicity of the compounds was in vitro evaluated in a hemolytic assay using human erythrocytes as a cell model. The in silico and in vitro study results indicate that the selected compound possesses an interesting biological activity and can be considered as potential drug design agent. Additionally, molecular docking was performed for the selected conjugate.