Design and Synthesis of Pentahydroxylhexylamino Acids and Their Effect on Lead Decorporation

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• 作者：Yuji Wang ; Lanrong Bi ; Baoguang Hou ; Yu Chen ; Ming Zhao ; Chao Wang ; Wei Wang ; Jingfang Ju ; Shiqi Peng
• 刊名：Chemical Research in Toxicology
• 出版年：2007
• 出版时间：April 2007
• 年：2007
• 卷：20
• 期：4
• 页码：609 - 615
• 全文大小：88K
• 年卷期：v.20,no.4(April 2007)
• ISSN：1520-5010

文摘

A series of enantiopure pentahydroxylhexylamino acids 4a-t were synthesized via an improved one-pot-three-step procedure. Their potential as antagonists for lead intoxication was investigated both invitro and in vivo. Lead decorporation assays in vivo confirmed that after treatment with 4a-t, the levelsof lead in treated mice were significantly reduced in the liver, kidney, bone, and brain compared to thosein the control group. In addition, the lead levels in feces and urine were significantly higher after treatmentwith 4a-t than those of the control group. In particular, the lead decorporation potency of compounds4b, 4i, 4j, and 4s were comparable or better than that of DL-penicillamine. Furthermore, new chelatingagents did not affect the levels of endogenous essential metals. The stability constants of the formed leadcomplexes of 4a-t were determined by potentiometric titration. It seems that the therapeutic efficiencyof the lead chelating agents depends on factors that affect the stability constants of the formed leadcomplexes. The membrane permeability of representative compounds was evaluated in a Caco-2 cellmonolayer. A good correlation between in vitro results and in vivo lead decorporation capacity of thechelating agents was observed. Some of these new pentahydroxylhexylamino acids (4b, 4i, 4j, and 4s)may be developed as effective lead chelating agents.