EVIDENCE FOR THE MODE OF ANTISCHISTOSOMAL ACTION OF HYCANTHONE
EVIDENCE FOR THE MODE OF ANTISCHISTOSOMAL ACTION OF HYCANTHONE
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DOI：
10.1016/0024-3205(85)90419-9
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发表时间：
1985-01-01
期刊：
影响因子：
6.1
通讯作者：
ARCHER, S
中科院分区：
文献类型：
--
作者：
CIOLI, D;PICAMATTOCCIA, L;ARCHER, S
证据支持的假设，即模式的行动，或其轻微的变化，建议由哈特曼等Hulbert帐户的致突变作用的海波龙（HC）是HC发挥其抗染色体活性的机制。HC被代谢活化为反应性酯，其在解离时使DNA烷基化。如果耐药体不受影响，因为它们不能将HC转化为反应性酯，则它们应在直接暴露于适当酯化的药物时被杀死。合成了Hycanthone N-甲基氨基甲酸酯（HNMC），并显示其与DNA结合并烷基化4-（对-硝基苄基）-吡啶。体外培养的HNMC不仅对敏感的S. mansoni（如HC），但也在HC抗性和未成熟的S. mansoni蠕虫和S.日本血蠕虫仅短暂抑制HC。在体外与HNMC接触1小时后，敏感和抗性的HNMC体无论是在培养中还是再移植到宿主动物中，均在3周内死亡。感染HC-耐药噬菌体的小鼠在体内HNMC给药后显示出急剧的蠕虫减少。
Evidence is presented which supports the hypothesis that the mode of action, or a slight variant thereof, suggested by Hartman et Hulbert to account for the mutagenic effects of hycanthone (HC) is the mechanism whereby HC exerts its antischistosomal activity. HC is metabolically activated to a reactive ester which, upon dissociation, akylates DNA. If resistant schistosomes are unaffected because they cannot convert HC to a reactive ester they should be killed upon direct exposure to an appropriately esterified drug. Hycanthone N-methylcarbamate (HNMC) was synthesized and shown to bind to DNA and alkylate 4-(p-nitrobenzyl)-pyridine. When tested with schistosomes kept in vitro, HNMC caused an irreversible inhibition of 3H-uridine incorporation not only in sensitive S. mansoni (as HC does) but also in HC-resistant and immature S. mansoni worms and S. japonicum worms which are only transiently inhibited by HC. After in vitro contact with HNMC for 1 h both sensitive and reistant schistosomes died in 3 wk if either kept in culture or re-transplanted into the host animal. Mice infected with HC-resistant schistosomes showed a drastic worm reduction after in vivo HNMC administration.