You Y J, Zheng X G, Yong K, Ahn B Z
College of Pharmacy, Chungnam National University, Taejon, Korea.
Arch Pharm Res. 1998 Oct;21(5):595-8. 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.
萘醌类化合物的谷胱甘肽缀合物形成速率、对DNA拓扑异构酶-I的抑制作用以及对L1210细胞的细胞毒性活性呈现相同顺序：5,8-二甲氧基-1,4-萘醌（DMNQ）>6-(1-羟乙基)-DMNQ>2-(1-羟乙基)-DMNQ；取代基，特别是2-取代基与细胞亲核试剂反应时的空间位阻必定是生物活性降低的主要原因。2-(1-羟乙基)-DMNQ乙酰化生成2-(乙酰氧基乙基)-DMNQ可增强生物活性；2-(1-羟乙基)-DMNQ不与谷胱甘肽和该酶反应，其半数有效剂量（ED50）为0.680微克/毫升，而2-(1-乙酰氧基乙基)-DMNQ的值为缀合物形成量0.14微摩尔、酶抑制作用的半数抑制浓度（IC50）值为81微摩尔以及细胞毒性的ED50为0.146微克/毫升。此外，2-(1-羟乙基)-DMNQ的乙酰化（T/C，119%）提高了荷S-180肿瘤小鼠的T/C值[2-(1-乙酰氧基乙基)-DMNQ的T/C为276%]。据推测，乙酰化导致的生物活性差异基于所谓的生物还原烷基化机制。
