Naphthazarin Derivatives: Synthesis, Inhibition of DNA Topoisomerase-I and Antitumor Activity

Ahn, B-Z; Kim, Y; You, Y-J; Chung, S-K; Kim, K-S; Song, G-Y; Sok, D-E

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자료유형: 학술대회자료

저자정보: Ahn, B-Z (College of Pharmacy, Chungnam National University) Kim, Y (College of Pharmacy, Chungnam National University) You, Y-J (College of Pharmacy, Chungnam National University) Chung, S-K (College of Pharmacy, Chungnam National University) Kim, K-S (College of Pharmacy, Chungnam National University) Song, G-Y (College of Pharmacy, Chungnam National University) Sok, D-E (College of Pharmacy, Chungnam National University)

저널정보: 한국응용약물학회 한국응용약물학회 춘계학술발표논문집 한국응용약물학회 1997년도 춘계학술대회

발행연도: 1997.1

수록면: 109 - 109 (1page)

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Inhibitory effect on DNA topoisomerase-I, rate of glutathione conjugation and cytotoxicity of naphthoquinone derivatives were correlated. During 5 min exposure of the derivatives to glutathione (GSH), it was found that 14% of 5,8-dimethoxy-1,4-naphthoquinone(DMNQ) was converted into a GSH-conjugate, whereas 5,8-dihydroxy-1,4-naphthoquinone(DHNQ) did not interact with GSH, implying that DMNQ exerted higher electrophilicity than DHNQ. However, DHNQ (IC$\_$50/, 0.15 ${\mu}$M) showed stronger cytotoxicity in L1210 cells than DMNQ(IC$\_$50/, 0.45 ${\mu}$M). The stronger cytotoxicity of DHNQ, compared to DMNQ, could be ascribed to more rapid redox cycling. Both naphthoquinones (IC$\_$50/, 60-65 ${\mu}$M) exhibiting about the same inhibitory effect on DNA topoisomerase-I were more potent than 1,4-naphthoquinone(1,4-NQ, IC$\_$50/, 134 ${\mu}$M). Thus, 5,8-oxy groups in the structure seem to be important for the inhibition of the enzyme. DMNQ showed a broader dose range while maintaining a good antitumor activity against S-180 fluid tumor. For these reasons, DMNQ was taken as useful pharmacophore for structural modification. Introduction of 1-hydroxyalkyl groups at C-2 of DMNQ lowered all of the activities mentioned above, while acetylation of 1-hydroxyalkyl moiety enhanced the activities by 4-5 times. Introduction of the same side chains at C-6 exhibited stronger activities than 2-substituted ones. Based on these results it was suggested that the quinonoid moiety in 6-substituted DMNQ was more exposed to cellular nucleophiles such as DNA, thiols of enzymes and so on. The synthesis of DHNQ or DMNQ derivatives are going on, and the corelationship between structure-activity will be discussed.

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