Microbial conversion of methyl- and methoxy- substituted derivatives of 5H-indolo[2,3-b]quinoline as a method of developing novel cytotoxic agents.
In furtherance of our structure-activity relationship studies on the antitumor activity of indolo[2,3-b]quinolines, novel cytotoxic derivatives bearing methyl groups at N-5, C-11, C-2 and/or C-9, as well as methoxy-groups at C-2 and/or C-9, were synthesized by the modified Graebe-Ullmann reaction. To elucidate the metabolic pathways of these compounds, zygomycete fungus Cunninghamella elegans ATCC 9245 (which is known to produce drug metabolites that are also formed in mammals) was used as a mimetic organism. Simultaneously, biotransformation of the same substrates was carried out with a microsomal fraction of rat liver. Three forms of microbial conversion were observed: hydroxylation of the aromatic ring or hydroxylation of the methyl group, and O-demethylation. The reaction proceeded regioselectively, and only positions C-2 and C-9 were affected in the indolo[2,3-b]quinoline system. The products formed were found to be identical with the metabolites generated by rat liver microsomes. The metabolites obtained displayed a cytotoxic activity in vitro against colon adenocarcinoma SW-707 and lung carcinoma A-549 (ID50 in the range 0.27-3.04 microM), which was as strong as that of the substrates. In the course of the further metabolic pathway study of indolo[2,3-b]quinolines we found that metabolites with a hydroxyl group in the aromatic system were transformed to non-cytotoxic polymeric products by multicopper oxidases: human ceruloplasmin or fungal laccase (used as mimetic enzyme), whereas metabolites with a hydroxymethyl group did not undergo such bioconversion. The last mentioned compounds can be regarded as a novel type of cytotoxic indolo[2,3-b]quinoline derivatives formed in metabolic processes.
Osiadacz
J
J
Institute of Immunology and Experimental Therapy; Polish Academy of Sciences, Wrocław, Poland.
Kaczmarek
L
L
Opolski
A
A
Wietrzyk
J
J
Marcinkowska
E
E
Biernacka
K
K
Radzikowski
C
C
Jon
M
M
Peczyńska-Czoch
W
W
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D001711:Biotransformation; D002570:Ceruloplasmin / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008862:Microsomes, Liver / Q000378:metabolism; D011804:Quinolines / Q000737:chemistry / Q000378:metabolism*; D051381:Rats
D000970:Antineoplastic Agents; D011804:Quinolines; D002570:Ceruloplasmin