Synthesis of cholic acid - cisplatin conjugates for potential liver selective drug uptake

The synthesis of cholic acid – cis-Pt conjugates is a promising attempt to reduce cis-Pt severe side effects. This conjugation makes the chemotherapeutic agent subject to enterohepatic circulation, conferring to the drug organotropic characteristics towards liver and intestine. Due to the bile acids´ specific transport pathways, the drug’s distribution in the organism is limited, which potentially reduces its side effects. Hence, the aim of this work is to synthesize cholic acid – cisplatin conjugates for a potential liver selective drug uptake. Here, the total synthesis of N-(2,3-diaminopropanamide)-3β-amine-7α,12α-cholic acid and the formation of a cis-Pt complex with it are described. Moreover, this work develops a method for the synthesis of two analogues, that include, respectively, a Gly-Gly peptide linker and the taurine moiety, which may have an influence on the cellular uptake and on the cytostatic activity. The innovative characteristic of the above-mentioned compounds is the position of the cis-Pt complex, which is formed, by introduction of a linker, on the 3-hydroxy position of the steroid system, instead of on the side chain on position 17. By keeping the acidic moiety on the side chain unmodified, the recognition of the complex by cellular transporters and its uptake may be enhanced, since the carboxylate group and especially the sulfonate group seem to play a crucial role in the interaction of bile acids with their cellular receptors, in particular NTCP and OATPs.