New propanoyloxy derivatives of 5¦Â-cholan-24-oic acid as drug absorption modifiers

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• 作者：Lenka Coufalová ; ^a ; ^{coufaloval@vfu.cz} ; Lech Mró ; zek^b ; Lucie Rá ; rová ; ^c ; Luká ; &scaron ; Pla?ek^d ; Radka Opat?ilová ; ^a ; Ji?&iacute ; Dohnal^a ; ^e ; Katar&iacute ; na Krá ; l&rsquo ; ová ; ^f ; Old?ich Paleta^g ; Vladim&iacute ; r Krá ; l^g ; Pavel Dra&scaron ; ar^g ; Josef Jamp&iacute ; lek^a ; ^e ; ^{josef.jampilek@gmail.com}
• 关键词：Cholic acid derivatives ; Lipophilicity ; Solubility ; Transdermal penetration enhancers ; Intestinal absorption promoters ; In vitro cytotoxicity
• 刊名：Steroids
• 出版年：2013
• 出版时间：May, 2013
• 年：2013
• 卷：78
• 期：5
• 页码：435-453
• 全文大小：1015 K

文摘

A series of final twelve propanoyloxy derivatives of 5¦Â-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 (R_M) 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 ¦ÌM), 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.