Potential antitumor agents: synthesis and biological properties of aliphatic amino acid 9-hydroxyellipticinium derivatives

Abstract

Aliphatic amino acids Gly, Ala, Val and Leu were conjugated to the antitumor drug N2-methyl-9-hydroxyellipticinium (NMHE) through a peroxidase-catalyzed oxidation reaction. NMR studies of the adducts so obtained indicated 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 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 .times. 105 to 5 .times. 105/M at pH 7.40. The presence of the amio acid moiety linked to NMHE results in a slight decrease of the cytotoxicity in L1210 cells in vitro (ID50 [minimum inhibitory dose] ranged from 0.20 to 0.50 .mu.M) as compared to NMHE (ID50 = 0.05 .mu.M); in a decrease of the antitumor efficiency in vivo against L1210 leukemia for Leu-NMHE and Val-NMHE (ILS [increase in life-span] at LD0/2 = 35 and 31%, respectively); in a suppression of the antitumor activity for Ala-NMHE and Gly-NMHE (ILS < 25%), (i.v.) in a strong increase in the bacteriostatic activity on the quaternary ammonium sensitive Escherichia coli BL101 strain and on Salmonella typhimurium TA98 strain. The bacateriostatic effect is direclty correlated with the lipophilic property of the drugs. These finding are discussed in terms of a structure-activity relationship.