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6-磷酸葡萄糖酸脱氢酶抑制剂4-磷酸-D-赤藓糖异羟肟酸的磷酸酯前药的合成及生物学评价

Synthesis and biological evaluation of phosphate prodrugs of 4-phospho-D-erythronohydroxamic acid, an inhibitor of 6-phosphogluconate dehydrogenase.

作者信息

Ruda Gian Filippo, Alibu Vincent P, Mitsos Christos, Bidet Olivier, Kaiser Marcel, Brun Reto, Barrett Michael P, Gilbert Ian H

机构信息

Division of Biological Chemistry and Molecular Microbiology, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee DD1 5EH, UK.

出版信息

ChemMedChem. 2007 Aug;2(8):1169-80. doi: 10.1002/cmdc.200700040.

DOI:10.1002/cmdc.200700040
PMID:17615587
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2248282/
Abstract

We have previously reported the discovery of potent and selective inhibitors of 6-phosphogluconate dehydrogenase, the third enzyme of the phosphate pentose pathway, from Trypanosoma brucei, the causative organism of human African trypanosomiasis. These inhibitors were charged phosphate derivatives with restricted capacity to enter cells. Herein, we report the synthesis of five different classes of prodrugs: phosphoramidate; bis-S-acyl thioethyl esters (bis-SATE); bis-pivaloxymethyl (bis-POM); CycloSaligenyl; and phenyl, S-acyl thioethyl mixed phosphate esters (mix-SATE). Prodrugs were studied for stability and activity against the intact parasites. Most prodrugs caused inhibition of the growth of the parasites. The activity of the prodrugs against the parasites appeared to be related to their stability in aqueous buffer.

摘要

我们之前曾报道过，从人类非洲锥虫病的病原体布氏锥虫中发现了6-磷酸葡萄糖酸脱氢酶（磷酸戊糖途径的第三种酶）的强效选择性抑制剂。这些抑制剂是带电荷的磷酸衍生物，进入细胞的能力有限。在此，我们报告了五类不同前药的合成：氨基磷酸酯；双-S-酰基硫代乙酯（双-SATE）；双新戊酰氧甲基（双-POM）；环水杨基酯；以及苯基、S-酰基硫代乙酯混合磷酸酯（混合-SATE）。对前药进行了稳定性和对完整寄生虫活性的研究。大多数前药导致寄生虫生长受到抑制。前药对寄生虫的活性似乎与其在水性缓冲液中的稳定性有关。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12c6/2699041/8d3362a0b2ee/cmdc0002-1169-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12c6/2699041/8b2238ffba3d/cmdc0002-1169-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12c6/2699041/daa202688d64/cmdc0002-1169-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12c6/2699041/c785392eac81/cmdc0002-1169-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12c6/2699041/cbd96037887d/cmdc0002-1169-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12c6/2699041/d3c58ec73b0b/cmdc0002-1169-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12c6/2699041/4924df2328c3/cmdc0002-1169-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12c6/2699041/dcb4272e9bdb/cmdc0002-1169-f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12c6/2699041/f4c3210abd7c/cmdc0002-1169-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12c6/2699041/8d3362a0b2ee/cmdc0002-1169-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12c6/2699041/8b2238ffba3d/cmdc0002-1169-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12c6/2699041/daa202688d64/cmdc0002-1169-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12c6/2699041/c785392eac81/cmdc0002-1169-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12c6/2699041/cbd96037887d/cmdc0002-1169-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12c6/2699041/d3c58ec73b0b/cmdc0002-1169-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12c6/2699041/4924df2328c3/cmdc0002-1169-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12c6/2699041/dcb4272e9bdb/cmdc0002-1169-f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12c6/2699041/f4c3210abd7c/cmdc0002-1169-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12c6/2699041/8d3362a0b2ee/cmdc0002-1169-f3.jpg

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