Design and synthesis of pentahydroxylhexylamino acids and their effect on lead decorporation.
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 in vitro and in vivo. Lead decorporation assays in vivo confirmed that after treatment with 4a-t, the levels of lead in treated mice were significantly reduced in the liver, kidney, bone, and brain compared to those in the control group. In addition, the lead levels in feces and urine were significantly higher after treatment with 4a-t than those of the control group. In particular, the lead decorporation potency of compounds 4b, 4i, 4j, and 4s were comparable or better than that of dl-penicillamine. Furthermore, new chelating agents did not affect the levels of endogenous essential metals. The stability constants of the formed lead complexes of 4a-t were determined by potentiometric titration. It seems that the therapeutic efficiency of the lead chelating agents depends on factors that affect the stability constants of the formed lead complexes. The membrane permeability of representative compounds was evaluated in a Caco-2 cell monolayer. A good correlation between in vitro results and in vivo lead decorporation capacity of the chelating agents was observed. Some of these new pentahydroxylhexylamino acids (4b, 4i, 4j, and 4s) may be developed as effective lead chelating agents.
Wang
Yuji
Y
College of Pharmaceutical Sciences, Peking University, Beijing 100083, People's Republic of China, College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, People's Republic of China.
Bi
Lanrong
L
Hou
Baoguang
B
Chen
Yu
Y
Zhao
Ming
M
Wang
Chao
C
Wang
Wei
W
Ju
Jingfang
J
Peng
Shiqi
S
D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D007854:Lead / Q000378:metabolism*; D051379:Mice; D015394:Molecular Structure
D000596:Amino Acids; D002614:Chelating Agents; D007854:Lead