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KMID : 0043319980210050595
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Archives of Pharmacal Research
1998 Volume.21 No. 5 p.595 ~ p.598
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Naphthazarin Derivatives: Synthesis, Cytotoxic Mechanism and Evaluation of Antitumor Activity
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You Young-Jae
Zheng Xiang-Guo
Kim Yong
Ahn Byung-Zun
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Abstract
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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-(-hydroxyethyl)-DMNQ did not react with GSH and the enzyme, and showed $ED_{50}$ of 0.146 mg/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.
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KEYWORD
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1,4-Naphthopuinone derivatives, Formation of glutathion conjugate, Antitumor activity, Inhibition of DNA topoisomerase-1, Structure-activity relationship, Steric hindrance, Bioreductive activation
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