Potential antitumor agents: synthesis and biological properties of aliphatic amino acid 9-hydroxyellipticinium derivatives.
Aliphatic amino acids glycine, alanine, valine, and leucine were conjugated to the antitumor drug N2-methyl-9-hydroxyellipticinium (NMHE) through a peroxidase-catalyzed oxidation reaction. NMR studies of the adducts so obtained have indicated (i) that the amino acids were linked to NMHE between the nitrogen of their primary amine and the C-10 position of the ellipticine ring and (ii) that a double bond was present between the nitrogen and the alpha-carbon of the amino acid moiety. All amino acid-NMHE adducts exhibit a higher lipophilic property than the parent compound (NMHE) directly correlated with the length of the aliphatic chain of the amino acids. The adducts interact with DNA through an intercalating process with apparent binding constant ranging from 2 X 10(5) to 5 X 10(5) M-1 at pH 7.40. The presence of the amino acid moiety linked to NMHE results (i) in a slight decrease of the cytotoxicity on L1210 cells in vitro (ID50 ranged from 0.20 to 0.50 microM) as compared to NMHE (ID50 = 0.05 microM), (ii) in a decrease of the antitumor efficiency in vivo against L1210 leukemia for leucine-NMHE and valine-NMHE (ILS at LD0/2 = 35% and 31%, respectively), (iii) in a suppression of the antitumor activity for alanine-NMHE and glycine-NMHE (ILS less than 25%), (iv) in a strong increase in the bacteriostatic activity on the quaternary ammonium sensitive Escherichia coli BL101 strain and on Salmonella typhimurium TA98 strain. The bacteriostatic effect is directly correlated with the lipophilic property of the drugs. These findings are discussed in terms of a structure-activity relationship.
D000470:Alkaloids / Q000138:chemical synthesis*; D000596:Amino Acids / Q000138:chemical synthesis / Q000627:therapeutic use; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D004611:Ellipticines / Q000138:chemical synthesis* / Q000627:therapeutic use; D007364:Intercalating Agents / Q000138:chemical synthesis; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D012995:Solubility
D000470:Alkaloids; D000596:Amino Acids; D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D004611:Ellipticines; D007364:Intercalating Agents