Modified bile acids: preparation of 7α,12α-dihydroxy-3β- and 7α,12α-dihydroxy-3α-(2-hydroxyethoxy)-5β-cholanic acid and their biological activity

Wess, G.; Kramer, Werner; Bartmann, W.; Enhsen, Alfons; Glombik, Heiner; Müllner, Stefan; Bock, Klaus; Dries, A.; Kleine, H.; Schmitt, W.

doi:10.1016/0040-4039(92)88048-a

Cited by 45 publications

(30 citation statements)

References 8 publications

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“…Therefore, we selected the most highly active site, hydroxyl-3 on the steroid ring, as connection point with the spacer and 5-FU [20]. In addition, because of the steric hindrance of the steroid ring, we extended the hydroxyl-3 and transformed it with ethylene glycol into a more active primary alcohol.…”

Section: Resultsmentioning

confidence: 99%

“…First, we performed the Nhydroxylmethylation of 5-FU 2 with formaldehyde and condensation with diacid monobenzyl esters to get 6a -e. Second, we catalyzed hydrogenolysis of 6a -e to get carboxylated 5-FU 7a -e [21]. 3-Hydroxyethyl cholic acid benzyl ester 5 was synthesized from cholic acid 1 [20]. After that, 8a -e were synthesized via acyl chloride from carboxylated 5-FU (7a -e) with a spacer chain [20].…”

Section: Resultsmentioning

confidence: 99%

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Synthesis and Characterization of New Liver Targeting 5‐Fluorouracil‐Cholic Acid Conjugates

Qian

et al. 2009

Archiv der Pharmazie

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The objective of this work was to develop a liver-specific antihepato carcinoma agent. A series of 5-fluorouracil / cholic acid conjugates (5-FU-cholic acid conjugates) were prepared and tested for their chemical characteristics and bio-distribution properties. The in-vitro stability trial showed 5-FU-cholic acid conjugates could be completely hydrolyzed by heating at 70 degrees C in an acidic solution, pH = 1, for 5 min. The fast and complete hydrolysis of these compounds could be compatible with a fast separation and analysis method to shorten the analysis time. The decomposition speeds of the 5-FU-cholic acid conjugates in different organs of mice at several time points after oral administration were evaluated by measuring the concentrations of regenerated 5-FU in organ tissue. The results were compared with those of the controls, which was a group of mice orally taking 5-FU. The concentrations of 5-FU in mice liver tissue were remarkably increased after oral administration of the prodrugs, and were much larger than if only orally administered 5-FU. The results suggested the feasibility to improve therapeutic efficiency of liver targeting treatments by using cholic acid as the vector of drugs.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Synthesis and Characterization of New Liver Targeting 5‐Fluorouracil‐Cholic Acid Conjugates

Qian

et al. 2009

Archiv der Pharmazie

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“…They have prepared bile acid-drug conjugates containing, for example, an alkylating cytostatic agent chlorambucil, collagen biosynthesis inhibiting oxaprolylpeptide, as well as cholesterol biosynthesis inhibitors HR780 and lovastatin (see Figure 4) [8,19,[104][105][106][107]. The spacer attached at C 3 -β position in these conjugates was commonly ω-aminoalkoxy residue [108,109], except in the case of oxaproline peptide derivative, which was attached to 3β-(5-aminopentoxy)-7α,12α-dihydroxy-5β-cholan-24-oic acid. Bile acid chlorambucil conjugates strongly inhibited the hepatic taurocholate transport in freshly isolated rat hepatocytes.…”

Section: Bile Acid-containing Prodrugsmentioning

confidence: 99%

Exploitation of Bile Acid Transport Systems in Prodrug Design

Sievänen

2007

Molecules

102

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Abstract:The enterohepatic circulation of bile acids is one of the most efficient recycling routes in the human body. It is a complex process involving numerous transport proteins, which serve to transport bile acids from the small intestine into portal circulation, from the portal circulation into the hepatocyte, from the hepatocyte into the bile, and from the gall bladder to the small intestine. The tremendous transport capacity and organ specificity of enterohepatic circulation combined with versatile derivatization possibilities, rigid steroidal backbone, enantiomeric purity, availability, and low cost have made bile acids attractive tools in designing pharmacological hybrid molecules and prodrugs with the view of improving intestinal absorption, increasing the metabolic stability of pharmaceuticals, specifically targeting drugs to organs involved in enterohepatic circulation, as well as sustaining therapeutically reasonable systemic concentrations of active agents. This article briefly describes bile acid transport proteins involved in enterohepatic circulation, summarizes the key factors affecting on the transport by these proteins, and reviews the use of bile acids and their derivatives in designing prodrugs capable of exploiting the bile acid transport system.

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“…1). With slight modifications, this synthesis followed the synthesis for the corresponding cholic acid derivatives (28). The modified bile salts were then conjugated with taurine (Fig.…”

Section: Synthesesmentioning

confidence: 99%

Synthesis of phospholipid-conjugated bile salts and interaction of bile salt-coated liposomes with cultured hepatocytes

Pütz

Schmider

Nitschke

et al. 2005

Journal of Lipid Research

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Hepatocyte pathology is central to many severe liver diseases. For optimal treatment and minimal adverse effects, drug concentrations in the target cell should be high while the systemic exposure to the drug should be as low as possible. For hepatocyte-specific drug delivery, hepatotropic liposomes represent an attractive strategy. Such hepatotropic liposomes need a signal on their surface targeting them selectively and specifically to hepatocytes. Hepatocyte-specific targeting of liposomes has been achieved by covalently linking the ligand of a hepatocyte-specific receptor to a lipid moiety. The most prominent targeted receptor is the hepatic asialoglycoprotein receptor, which has been targeted by various galactosyllipids (1, 2) or by asialofetuin, a glycoprotein (3). Glycyrrhizin (4) and a soybean-derived sterylglucoside mixture (5) have been used to target hepatocytes via receptors that have not yet been identified at the molecular level. To date, all of these receptors lead to the endocytosis of bound liposomes.After targeting the liposomes to endocytosing receptors, Abbreviations: BSL, bile salt-bearing

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Modified bile acids: preparation of 7α,12α-dihydroxy-3β- and 7α,12α-dihydroxy-3α-(2-hydroxyethoxy)-5β-cholanic acid and their biological activity

Cited by 45 publications

References 8 publications

Synthesis and Characterization of New Liver Targeting 5‐Fluorouracil‐Cholic Acid Conjugates

Synthesis and Characterization of New Liver Targeting 5‐Fluorouracil‐Cholic Acid Conjugates

Exploitation of Bile Acid Transport Systems in Prodrug Design

Synthesis of phospholipid-conjugated bile salts and interaction of bile salt-coated liposomes with cultured hepatocytes

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