Metabolism of cytostatically active 6-aminobenzo[c]phenanthridines by human and porcine hepatic microsomes and recombinant cytochrome P450 enzymes

Abstract

A new and convenient two-step synthesis of 11-substituted 6-amino-11,12-dihydrobenzo[c]phenanthridines and 6-aminobenzo[c]phenanthridines (BPs and BP-Ds) was developed recently in the authors' laboratory. These compounds revealed a high antitumoral activity in in vitro and in vivo test systems. In particular, 11-phenyl-substituted derivatives with two or three methoxy groups showed good activity. It was not clear if the dihydro-derivatives (BPs) were transformed enzymatically into the phenanthridines (BP-Ds), thus acting as prodrugs. The in vitro metabolism of several of these cytostatically active 6-aminobenzo[c]phenanthridines was investigated using human and porcine liver microsomes and a range of expressed human cytochrome P450 enzymes. High-performance liquid chromatography and liquid chromatography-mass spectrometry analysis were used for the quantification and structural identification of the observed metabolites. Aromatic hydroxylation was observed to be the major metabolic pathway in addition to a number of other metabolites. The formation of N-hydroxy- and 6-oxo-derivatives was detected only in very small amounts. BP derivatives are not prodrugs of BP-Ds and no significant differences between human and porcine microsomes were observed, confirming the pig as a good model for metabolism studies of these compounds.

11‐Substituted Benzo[c]phenanthridines: New Structures and Insight into Their Mode of Antiproliferative Action

“…The substituent at position 6 can be completely removed by reduction of the thione, leading to structures 26 and 27 (BPE and BP‐DE series) with the e liminated substituent. For a few examples, we showed that alternatively the oxo group can be transformed into the chlorine substituent, which allowed introduction of the hydroxylamine group at position 6, for example . More specialized transformations included formation of the benzo[ c ]phenanthridine skeleton, which means a phenanthridine bearing a proton at position 11.…”

“…For af ew examples, we showed that alternatively the oxo group can be transformed into the chlorine substituent,w hich allowed introduction of the hydroxylamine group at position 6, for example. [14] More specialized transformations included formation of the benzo[c]phenanthridine skeleton, which meansaphenanthridine bearing ap rotona t position1 1. This structure is accessible by using formaldehyde as startingm aterialw ith subsequento xidation and cleavage of the substituent at position6.…”