The biooxidation of cytotoxic ellipticine derivatives: a key to structure-activity relationship studies?
In the family of ellipticine derivatives, those with an amino-phenol or a masked amino-phenol structure are among the most cytotoxic compounds. Preliminary studies on 9-hydroxy- or 9-methoxyellipticines have shown that these molecules behave as "pro-alkylating" agents. In order to rationalize the "biooxidative alkylation" process for various ellipticine derivatives, we report in the present article (i) their electrochemical oxidation parameters, (ii) their biochemical oxidation, (iii) the ability of the oxidized forms to form adducts with nucleophiles, (iv) the biological activities, and (v) the electronic properties of oxidized forms. We present some possible correlations between the oxidizability, the electrophilicity of the oxidized derivatives, and the biological activities of the corresponding drugs.
Meunier
G
G
Laboratoire de Pharmacologie et de Toxicologie Fondamentales, Toulouse, France.
De Montauzon
D
D
Bernadou
J
J
Grassy
G
G
Bonnafous
M
M
Cros
S
S
Meunier
B
B
D000470:Alkaloids / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000378:metabolism*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004611:Ellipticines / Q000031:analogs & derivatives / Q000378:metabolism*; D010084:Oxidation-Reduction; D012997:Solvents; D013329:Structure-Activity Relationship
D000470:Alkaloids; D000970:Antineoplastic Agents; D004611:Ellipticines; D012997:Solvents; C011521:olivacine