Novel bile acid derivatives (BANBs) with cytostatic activity obtained by conjugation of their side chain with nitrogenated bases

Drug targeting may contribute to overcoming resistance to chemotherapy and to reducing side effects. Here, by conjugating a nitrogenated base (NB) to the side chain of a bile acid (BA) moiety, we have synthesized and evaluated six novel compounds, designated BANB-1 to -6, with potential cytostatic activity and vectoriality toward enterohepatic tumors. These compounds were purified by liquid chromatography and their purity was checked by TLC and HPLC before being chemically characterized using IR, 1H/13C NMR and FAB-MS. Using several cell lines – HepG2 (human hepatoblastoma), LS 174T and Caco-2 (human colon adenocarcinoma), Hepa 1-6 (mouse hepatoma), McA-RH7777 (rat hepatoma), CCRF S-180 II (mouse sarcoma) and CHO (Chinese hamster ovary) – their effect on cell viability was measured with the formazan test after drug exposure for 6 h (cytotoxic effect) or 72 h (cytostatic effect). A weak cytostatic effect of BANB-1, BANB-2 and BANB-3 was detected even in CHO cells stably transfected with rat bile acid transporters (Ntcp and Oatp1/1a1). In contrast, BANB-4, BANB-5 and BANB-6, similarly to cisplatin, showed strong cytostatic effects, together with mild non-specific toxicity. BANB-6 was effective even against Hepa 1-6/R cells, which were partly resistant to cisplatin. Treatment with BANB-6, but not cisplatin, was able to prolong the life span of Nude mice bearing tumors formed by Hepa 1-6/R cells orthotopically implanted in the liver. In conclusion, our results support the hypothesis that cytostatic bile acid derivatives such as BANB-6 may offer a useful pharmacological strategy for the treatment of tumors of the enterohepatic circuit.