title: New propanoyloxy derivatives of 5β-cholan-24-oic acid as drug absorption modifiers.
abstract: A series of final twelve propanoyloxy derivatives of 5β-cholan-24-oic acid (O-propanoyl derivatives of cholic acid) as potential drug absorption modifiers (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 (log S), 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 leukemia cell line and breast adenocarcinoma cell line. One compound showed selective cytotoxicity against human skin fibroblast cells and another compound possessed the highest cytotoxicity against all the tested cell lines. Only one compound expressed anti-proliferative effect on leukemia cancer 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>37 μM), 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 enhancement effect are discussed in this article.
authors: Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Palackeho 1/3, 612 42 Brno, Czech Republic. coufaloval@vfu.cz
authors: Lenka
authors: L
authors: Coufalová
authors: Lech
authors: L
authors: Mrózek
authors: Lucie
authors: L
authors: Rárová
authors: Lukáš
authors: L
authors: Plaček
authors: Radka
authors: R
authors: Opatřilová
authors: Jiří
authors: J
authors: Dohnal
authors: Katarína
authors: K
authors: Král'ová
authors: Oldřich
authors: O
authors: Paleta
authors: Vladimír
authors: V
authors: Král
authors: Pavel
authors: P
authors: Drašar
authors: Josef
authors: J
authors: Jampílek
mesh_terms: D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002793:Cholic Acids / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007408:Intestinal Absorption / Q000187:drug effects*; D010539:Permeability / Q000187:drug effects; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010599:Pharmacokinetics; D012869:Skin Absorption / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D002793:Cholic Acids; D004364:Pharmaceutical Preparations; C007036:cholanic acid