Antitumor agent 9-ethylamino-4-methyl-1-nitroacridine, C-1748, belongs to a new set of antitumor derivatives developed in our laboratory and was selected to preclinical studies. Metabolic pathway of a representative 9-amino-1-nitroacridine with rat microsomes was proposed earlier [1]. Compound C-1748, which is less toxic than its analog without 4-methyl group, C-857, was shown to be less reactive with human and rat liver microsomes as well as with human E. coli recombinant CYPs [2]. Therefore, we hypothesized that metabolism of C­1748 is a probable reason of its reduced toxicity in animals. In this work we present the studies on metabolic transformations of C-857 and C-1748 in human hepatoma HepG2 cells. The investigations aimed to evaluate whether any new metabolic products are formed in tumor cells in comparison with metabolites identified previous with microsomal and hepatic recombinant enzymes, and whether the differences in HepG2 metabolism between C-857 and C-1748 are similar to those observed earlier for enzymatic transformations. HepG2 cells were incubated with specified concentration of C-857 and C-1748 for 3, 4, 6 and 12 hours. Metabolites were extracted with methanol and RP-HPLC analyses of extracts were performed with UV-VIS and ESI-MS detection. Another part of HepG2 cells incubated with studied drugs were examined under fluorescence microscopy. The obtained results demonstrated that several new metabolites were formed in HepG2 complay to model enzymatic systems. On the other hand, at least one metabolite found in HepG2 cells was identical to that identified previous in enzymatic systems. It was a derivative with additional pyrazole ring closed between nitrogen atoms at positions 1 and 9 of acridine ring. Metabolites of C-857 extracted from HepG2 cells were clearly observed after 3 and 4 hours of incubations, whereas 6 and 12 hours of incubations gave lower concentrations of products. In the contrary, metabolites of C-1748 were observed after prolonged incubation with the drug, until 12 hours. In conclusion, the results showed the presence of reactive metabolites of 9-amino-1-nitroacridines in human hepatoma HepG2 cells and demonstrated also that C-1748 is less reactive than C-857 in this cellular model.

References

[1.] K. Gorlewska, Z. Mazerska, P. Sowiński and J. Konopa, Products of metabolic activation of the antitumor drug ledakrin (Nitracrine) in vitro, Chem. Res. Toxicol., 14, 1-10, (2001)

[2.] A. Wiśniewska, A. Chrapkowska, J. Konopa and Z. Mazerska, Selectivity in CYP mediated metabolism of antitumor 9-amino-1-nitroacridine derivative, C-1748 (Capridine-beta), an agent under phase I clinical trials, Books of Abstracts, 15th International Conference on Cytochromes P450, Bled, Slovenia, June 2007, p.190.

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