Bile acids
Bile acids play a vital role in the emulsification of lipophilic nutrients promoting their resorption and digestion in the gastrointestinal tract. As part of the enterohepatic cycle, bile acids are transported between intestine, liver, and gall bladder.[1,2] These transport processes can occur either via passive diffusion or via active transport facilitated by specific bile acid carrier proteins.[3] Metabolization of the primary bile acids cholic acid and chenodeoxycholic acid to their secondary counterparts deoxycholic acid and lithocholic acid occurs during their enterohepatic circulation. Moreover, bile acids get conjugated to the amino acid glycine or the amino sulfonic acid taurine to promote their active transport.[1,2]
Transport studies of bile acids are commonly performed using their respective radio-labelled derivatives (e.g. [3H] taurocholic acid). Unfortunately, these bile acid derivatives entail the compliance of severe safety protocols and high costs.[4] The attachment of a fluorophore to the 3’ hydroxy group of the steroid core displays a promising alternative for monitoring enterohepatic transport.[5,6] Thereby, the fluorophore 4-nitrobenzo-2-oxa-1,3-diazole (NBD) protrudes due to its low sterical impact and high quantum yield.[7] Hence, our research focuses on the synthesis of NBD-bile acid conjugates and the analysis of their transport behaviour and transporter specificity.
The concept of carrier-drug conjugates refers to the transport of medically useful molecules into a specific tissue, resulting in higher bioavailability, increased drug efficacy, and reduced side effects.[8,9] Beneficial requirement is the substrate specificity for certain receptors in the cell membrane to invade cells located in the targeted tissue.[8] In this project, cholic acid is exploited as the carrier molecule for 3-Chloropiperidines, which are known for alkylating the DNA inhibiting the replication and ultimately lead to the apoptosis of the cell.[10] The aim of the project is a specific transportation of DNA alkylating agents into liver cells. Respective carrier-drug conjugates which are linked via different functional groups of cholic acid can be synthesized. The synthesis is followed up by a biological comparison of the molecules’ transport capabilities into the cell and cytotoxicity.
Both projects are performed in cooperation with the group of Prof. Dr. Joachim Geyer (Institute of Toxicology and Pharmacology, University Giessen).
[1] T. Da Claro Silva et al., Molecular Aspects of Medicine 2013, 34, 252.
[2] M. C. Di Gregorio et al., International Journal of Molecular Sciences 2021, 22.
[3] D. W. Russell et al., Biochemistry 1992, 31, 4737.
[4] P. Milkiewicz et al., Journal of Hepatology 1997, 27, 1106–1109.
[5] T. de Bruyn et al., Journal of Pharmaceutical Sciences 2014, 103, 1872–1881.
[6] E. Petzinger et al., Hepatology 1999, 30, 1257–1268.
[7] U. Schramm et al., Journal of Lipid Research 1991, 32, 1769–1779.
[8] R. Paschke et al., Current medicinal chemistry 2003, 10, 2033.
[9] G. A. Kullak-Ublick et al., Gastroenterology 1997, 113, 1295.
[10] I. Zuravka et al., ChemMedChem 2014, 9 (9), 2178–2185.
| Projekt director: | Prof. Dr. Richard Göttlich |
| Co-workers: | M. Sc. Celine Drossel |
| M. Sc. Jana Semmler |