title: New polyfluorothiopropanoyloxy derivatives of 5β-cholan-24-oic acid designed as drug absorption modifiers.
abstract: 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 (1)H NMR, (13)C 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.
authors.affiliation: BorsodChem MCHZ, s.r.o., Chemická 1/2039, 709 03 Ostrava-Mariánské Hory, Czech Republic. lech.mrozek@email.cz
authors.forename: Lech
authors.initials: L
authors.lastname: Mrózek
authors.forename: Lenka
authors.initials: L
authors.lastname: Coufalová
authors.forename: Lucie
authors.initials: L
authors.lastname: Rárová
authors.forename: Lukáš
authors.initials: L
authors.lastname: Plaček
authors.forename: Radka
authors.initials: R
authors.lastname: Opatřilová
authors.forename: Jiří
authors.initials: J
authors.lastname: Dohnal
authors.forename: Katarína
authors.initials: K
authors.lastname: Kráľová
authors.forename: Oldřich
authors.initials: O
authors.lastname: Paleta
authors.forename: Vladimír
authors.initials: V
authors.lastname: Král
authors.forename: Pavel
authors.initials: P
authors.lastname: Drašar
authors.forename: Josef
authors.initials: J
authors.lastname: Jampílek
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002793:Cholic Acids / Q000737:chemistry*; D005079:Excipients / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity; D057927:Hydrophobic and Hydrophilic Interactions; D007408:Intestinal Absorption; D061986:MCF-7 Cells; D008567:Membranes, Artificial; D010539:Permeability; D011422:Propionates / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity; D012869:Skin Absorption; D012995:Solubility
chemical_list: D002793:Cholic Acids; D005079:Excipients; D006845:Hydrocarbons, Fluorinated; D008567:Membranes, Artificial; D011422:Propionates; C007036:cholanic acid
keywords: Cholic acid derivatives; Intestinal absorption promoters; Transdermal penetration enhancers