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Studies on synthesis of inhibitors of sulfotransferases in mucopolysaccharide biosynthesis and application of the inhibitors to substrate deprivation therapy for mucopolysaccharidoses

粘多糖生物合成磺基转移酶抑制剂的合成及其在粘多糖病底物剥夺治疗中的应用研究

基本信息

批准号：
14370761
负责人：
NISHIMURA Yoshio
金额：
$ 2.88万
依托单位：
Microbial Chemistry Research Foundation
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

gem-Diamine 1-N-iminosugars related to L-iduronic acid and D-glucosamine were investigated to inhibit iduronate 2-O-sulfotransferase (2-O-ST) and N-deacetylase/N-sulfotransferase (NDST) for the GAG-chain biosynthesis in Hunter and Sanfilipo syndrome, respectively. Within the three years, about 60 compounds were synthesized and evaluated as inhibitors of 2-O-ST and NDST using an in vitro enzyme assay. Two iminosugars containing guanidine groups acted as potent inhibitors of 2-O-ST. Two inhibitors were subsequently tested in vivo as inhibitors of glycosaminoglycan biosynthesis using (i) biotinylated FGF-2 (ii) total ^<35>SO_4-labeling of the glycosaminoglycan chains and (iii) ^3H-GlcN-labeling of the glycosaminoglycan chains followed by disaccharide analysis. However, none of the active in vitro compounds were inhibitors of GAG biosynthesis in vivo. Both compounds were also found non-toxic to CHO-K1 cells. The lack of activity most likely reflects poor uptake by cells due to the positively charged guanidine moiety. These biological studies may require introduction of substituents and/or removal blocking groups to increase the permeability of the compounds to cell membranes.This is the first evidence that gem-diamine 1-N-iminosugars act as inhibitors of an enzyme involved in heparan sulfate synthesis. This suggests that the combination of substrate deprivation therapy and enzyme replacement therapy would also be anticipated.

研究了与L-艾杜糖醛酸和D-氨基葡萄糖相关的GEM-二胺-1-N-亚胺糖分别抑制Hunter综合征和Sanfilipo综合征患者Gag链生物合成的艾杜酸2-O-磺基转移酶(2-O-ST)和N-脱乙酰酶/N-磺基转移酶(NDST)。在三年的时间里，合成了约60个化合物，并通过体外酶试验对其作为2-O-ST和NDST的抑制剂进行了评价。两个含胍基团的亚氨糖是2-O-ST的有效抑制剂。随后，通过(I)生物素化的成纤维细胞生长因子-2(Ii)总糖胺聚糖链的硫酸标记和(Iii)糖胺聚糖链的~3H-GlcN标记和双糖分析，两种抑制剂作为糖胺多糖生物合成的抑制剂在体内被测试。然而，所有的体外活性化合物都不是体内GAG生物合成的抑制剂。这两种化合物对CHO-K1细胞也没有毒性。活性的缺乏很可能反映了由于带正电的胍部分而被细胞摄取得很差。这些生物学研究可能需要引入取代基和/或去除封闭基团来增加化合物对细胞膜的通透性。这是第一个证据表明吉姆二胺1-N-亚氨糖作为参与硫酸乙酰肝素合成的酶的抑制剂。这表明底物剥夺疗法和酶替代疗法的结合也是可以预见的。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Synthesis and inhibitory activity of 8-substituted 2-deoxy-β-KD0 against CMP-KD0 synthetase

8-取代2-脱氧-β-KD0的合成及其对CMP-KD0合成酶的抑制活性

DOI：
发表时间：
2006
期刊：
Natural Products Research (in press)
影响因子：
0
作者：
Hayamitsu Adachi
通讯作者：
Hayamitsu Adachi

K.Kondo, H.Doi, H.Adachi, Y.Nishimura: "Synergistic effect of CMP/KDO synthase inhibitors with antimicrobial agents on inhibition of production and release of Vero toxin by enterohaemorrhagic Escherichia coli O157-H7"Bioorg.Med.Chem.Lett.. 14. 467-470 (20

K.Kondo、H.Doi、H.Adachi、Y.Nishimura：“CMP/KDO 合酶抑制剂与抗菌药物对抑制肠出血性大肠杆菌 O157-H7 产生和释放 Vero 毒素的协同作用”Bioorg.Med.Chem

DOI：
发表时间：
期刊：
影响因子：
0
作者：
通讯作者：

Synergistic effect of CMP/KDO synthase inhibitors with antimicrobial agents on inhibition of production and release of Vero toxin by enterohaemorrhagic Esherichia coli O157-H7

CMP/KDO合酶抑制剂与抗菌药物对抑制肠出血性大肠杆菌O157-H7产生和释放Vero毒素的协同作用

DOI：
发表时间：
2004
期刊：
Bioorganic & Medicinal Chemistry Letters 14
影响因子：
0
作者：
Ken-ichiro Kondo et al.
通讯作者：
Ken-ichiro Kondo et al.

Synthesis and evaluation of gem-diamine 1-N-iminosugars related to L-iduronic acid as inhibitors of heparan sulfate 2-O-sulfotransferase

L-艾杜糖醛酸相关偕二胺1-N-亚氨基糖作为硫酸乙酰肝素2-O-磺基转移酶抑制剂的合成与评价

DOI：
发表时间：
2006
期刊：
Bioorganic & Medicinal Chemistry Letters 16
影响因子：
0
作者：
Ishikawa T.;Tsuji A.;Inui K.;Sai Y.;Anzai N.;Wada M.;Endou H.;Sumino Y.;Jillian R.Brown et al.
通讯作者：
Jillian R.Brown et al.

Synergistic effect of CMP/KD0 synthase inhibitors with antimicrobial agents on inhibition of production and release of Vero toxin by enterohaemorrhagic Esherichia coli 0157-H7

CMP/KD0合酶抑制剂与抗菌药物对抑制肠出血性大肠杆菌0157-H7产生和释放Vero毒素的协同作用