New polyfluorothiopropanoyloxy derivatives of 5β-cholan-24-oic acid designed as drug absorption modifiers

• Published in: Steroids 2013-09, Vol.78 (9), p.832-844
• Main Authors: Mrózek, Lech, Coufalová, Lenka, Rárová, Lucie, Plaček, Lukáš, Opatřilová, Radka, Dohnal, Jiří, Kráľová, Katarína, Paleta, Oldřich, Král, Vladimír, Drašar, Pavel, Jampílek, Josef
• Format: Article
• Language: English
• Subjects: Cell Proliferation - drug effects; Cell Survival - drug effects; Cholic acid derivatives; Cholic Acids - chemistry; Excipients - chemical synthesis; Excipients - metabolism; Excipients - toxicity; Fibroblasts - drug effects; Fibroblasts - metabolism; Humans; Hydrocarbons, Fluorinated - chemical synthesis; Hydrocarbons, Fluorinated - metabolism; Hydrocarbons, Fluorinated - toxicity; Hydrophobic and Hydrophilic Interactions; Intestinal Absorption; Intestinal absorption promoters; MCF-7 Cells; Membranes, Artificial; Permeability; Propionates - chemical synthesis; Propionates - metabolism; Propionates - toxicity; Skin Absorption; Solubility; Transdermal penetration enhancers
• ISSN: 0039-128X; 1878-5867
• DOI: 10.1016/j.steroids.2013.05.012

•5β-Cholan-24-oic acid derivatives: synthesis, lipophilicity, solubility.•Transdermal penetration enhancers.•Intestinal absorption promoters.•In vitro cytotoxicity.•Relationships between the structure and the enhancement effects. A series of final six propanoyloxy derivatives of 5β-cholan-24-oic acid (tridecafluoroctylsulfanyl- and tridecafluoroctylsulfinylethoxycarbonylpropanoyloxy derivatives) as potential drug absorption promoters (skin penetration enhancers, intestinal absorption promoters) was generated by multistep synthesis. Structure confirmation of all generated compounds was accomplished by 1H NMR, 13C NMR, IR and MS spectroscopy methods. All the prepared compounds were analyzed using RP-TLC, and their lipophilicity (RM) was determined. The hydrophobicity (log P), solubility (logS), polar surface area (PSA) and molar volume (MV) of the studied compounds were also calculated. All the target compounds were tested for their in vitro transdermal penetration effect and as potential intestinal absorption enhancers. The cytotoxicity of all the evaluated compounds was evaluated against normal human skin fibroblast cells. Their anti-proliferative activity was also assessed against human cancer cell lines: T-lymphoblastic leukaemia cell line and breast adenocarcinoma cell line. One compound showed high selective cytotoxicity against human skin fibroblast cells and another compound possessed high cytotoxicity against breast adenocarcinoma cell line and skin fibroblast cells. Only one compound expressed anti-proliferative effect on leukaemia and breast adenocarcinoma cells without affecting the growth of normal cells, which should be promising in potential development of new drugs. Most of the target compounds showed minimal anti-proliferative activity (IC50>37μM), indicating they would have moderate cytotoxicity when administered as chemical absorption modifiers. The relationships between the lipophilicity/polarity and the chemical structure of the studied compounds as well as the relationships between their chemical structure and penetration enhancement effect are discussed in this article.