Naphthazarin derivatives: synthesis, cytotoxic mechanism and evaluation of antitumor activity

• Published in: Archives of pharmacal research 1998-10, Vol.21 (5), p.595-598
• Main Authors: You, Y J, Zheng, X G, Yong, K, Ahn, B Z
• Format: Article
• Language: English
• Subjects: Acetylation; Animals; Antineoplastic Agents, Phytogenic - chemical synthesis; Antineoplastic Agents, Phytogenic - pharmacology; Cell Survival - drug effects; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Glutathione - chemistry; Leukemia L1210 - drug therapy; Male; Mice; Mice, Inbred ICR; Naphthoquinones - chemical synthesis; Naphthoquinones - pharmacology; Oxidation-Reduction; Sarcoma 180 - drug therapy; Topoisomerase I Inhibitors
• ISSN: 0253-6269; 1976-3786
• DOI: 10.1007/BF02975381

The rate of the GSH conjugate formation, the inhibition of DNA topoisomerase-I and the cytotoxic activity against L1210 cells of the naphthoquinones showed the same order; 5,8-dimethoxy-1,4-naphthoquinone (DMNQ) > 6-(1-hydroxyethyl)-DMNQ > 2-(1-hydroxyethyl)-DMNQ; the steric hindrance of the substituents, particularly 2-substutuent, in reacting with cellular nucleophiles must be the main cause for lowering the bioactivities. Acetylation of 2-(1-hydroxyethyl)-DMNQ producing 2-(acetyloxyethyl)-DMNQ potentiated the bioactivities; 2-(1-hydroxyethyl)-DMNQ did not react with GSH and the enzyme, and showed ED50 of 0.680 microgram/ml, whereas the values of 2-(1-acetyloxyethyl)-DMNQ were the conjugate formation of 0.14 microM, IC50 value of 81 microM for the enzyme inhibition and ED50 of 0.146 microgram/ml for the cytotoxcity. Furthermore, the acetylation 2-(1-hydroxyethyl)-DMNQ (T/C, 119%) enhanced the T/C values for the mice bearing S-180 tumor [T/C of 2-(1-acetyloxyethyl)-DMNQ, 276%]. It was assumed that the difference in bioactivities ensued by acetylation was based on the mechanism of the so-called bioreductive alkylation.