title: Investigation of new acyloxy derivatives of cholic acid and their esters as drug absorption modifiers.
abstract: Skin penetration enhancers are used in the formulation of transdermal delivery systems for drugs that are otherwise not sufficiently skin-permeable. Intestinal absorption promoters/enhancers are used as excipients in oral formulations of poorly oral-bioavailable drugs. Series of fourteen acyloxy derivatives of 5β-cholic acid as potential drug absorption modifiers was generated by multistep synthesis. The synthesis of all newly prepared compounds is presented here. 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 (R(M)) was determined. The hydrophobicity (logP) and solubility (logS) of the studied compounds were also calculated using two commercially available programs. All the target compounds were tested for their in vitro transdermal penetration activity and as potential intestinal absorption enhancers. The anti-proliferative activity of all the final compounds was also assessed against the human cancer cell lines: T-lymphoblastic leukemia cell line and the breast adenocarcinoma cell line. Their cytotoxicity was also evaluated against the normal human skin fibroblast cells. Two compounds showed anti-proliferative effect on 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 (IC(50)>37 μM), indicating they would have low cytotoxicity when administered as chemical absorption modifiers. The relationships between the lipophilicity and the chemical structure of the studied compounds as well as the relationships between their chemical structure and enhancement effects are discussed in this article.
authors.affiliation: BorsodChem MCHZ, s.r.o., Chemicka 1/2039, 709 03 Ostrava-Marianske Hory, Czech Republic.
authors.forename: Lech
authors.initials: L
authors.lastname: Mrózek
authors.forename: Lenka
authors.initials: L
authors.lastname: Dvořáková
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Mandelová
authors.forename: Lucie
authors.initials: L
authors.lastname: Rárová
authors.forename: Anna
authors.initials: A
authors.lastname: Řezáčová
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: 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: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D019826:Cholic Acid / Q000009:adverse effects / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D004952:Esters / Q000009:adverse effects / Q000737:chemistry*; D005079:Excipients / Q000009:adverse effects / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D009682:Magnetic Resonance Spectroscopy; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D012869:Skin Absorption / Q000187:drug effects; D013329:Structure-Activity Relationship; D013552:Swine; D013806:Theophylline / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D004952:Esters; D005079:Excipients; D013806:Theophylline; D019826:Cholic Acid