Naphthazarin derivatives: synthesis, cytotoxic mechanism and evaluation of antitumor activity.
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.
You
Y J
YJ
College of Pharmacy, Chungnam National University, Taejon, Korea.
Zheng
X G
XG
Yong
K
K
Ahn
B Z
BZ
D000107:Acetylation; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D005978:Glutathione / Q000737:chemistry; D007939:Leukemia L1210 / Q000188:drug therapy; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009285:Naphthoquinones / Q000138:chemical synthesis* / Q000494:pharmacology*; D010084:Oxidation-Reduction; D012510:Sarcoma 180 / Q000188:drug therapy; D059004:Topoisomerase I Inhibitors
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D009285:Naphthoquinones; D059004:Topoisomerase I Inhibitors; C005503:naphthazarin; D005978:Glutathione