权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Development of zinc chelators with protein specificity aiming at molecular target therapy of cancer

开发针对癌症分子靶向治疗的蛋白质特异性锌螯合剂

基本信息

批准号：
17390030
负责人：
OTSUKA Masami
金额：
$ 10.12万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390030/
关键词：
cancer zinc protein chelator molecular target

项目摘要

The present research aims at the development of inhibitors of zinc proteins designed by combing a zinc chelator and a protein recognition moiety. We were interested farnesyltransferase and ADAM family protease as zinc proteins to be inhibited.Synthetic study of farnesyltransferase inhibitorsA zinc protein farnesyltransferase catalyzes the farnesylation of an oncogene product Ras to induce the oncogenic function of Ras. The objective of the present study is to obtain inhibitors by introducing a farnesyl phosphate, a farnesyltransferase-recognition moiety, into a zinc chelator comprising a pyridine and cysteamine side chains.Considering the instability of the farnesyl group, a 4-aminopyridine chelator was first synthesized. The farnesyl moiety was then successfully introduced by the formation of phosphoramide linkage between the 4-amino group and farnesyl phosphate.Synthetic study of ADAM family protease inhibitorsAdhesive molecule CD44 is known to be closely related to proliferation, invasion and metastasis of cancer cells. The cell adhesion and the cell movement are due to the cleavage of the extracellular domain of the CD44 by ADAM family proteases, resulting the cancer metastasis and invasion.The present study employed marimastat, an ADAM 30 inhibitor, as the ADAM family protease recognition moiety. Thus (D)-Tartrate was converted into the corresponding eposide and an isobutyl group was introduced to obtain a key intermediate, a marimastat precursor. The coupling of the marimastat moiety thus obtained and the zinc chelator was attempted.

本研究旨在结合锌螯合剂和蛋白质识别片段设计锌蛋白抑制剂。我们对法尼基转移酶和ADAM家族蛋白酶作为锌蛋白被抑制感兴趣。法尼基转移酶抑制剂的合成研究sa锌蛋白法尼基转移酶催化致癌基因产物Ras的法尼基化，诱导Ras的致癌功能。本研究的目的是通过在含有吡啶和半胱胺侧链的锌螯合剂中引入法尼基磷酸（法尼基转移酶识别片段）来获得抑制剂。考虑到法尼基的不稳定性，首次合成了4-氨基吡啶螯合剂。然后通过在4-氨基和磷酸法尼酯之间形成磷酰胺键成功地引入了法尼酯基部分。ADAM家族蛋白酶抑制剂和黏附分子CD44的合成研究已被证实与癌细胞的增殖、侵袭和转移密切相关。细胞的粘附和运动是由于ADAM家族蛋白酶对CD44细胞外结构域的切割，导致癌细胞转移和侵袭。本研究采用ADAM 30抑制剂marimastat作为ADAM家族蛋白酶识别片段。因此，(D)-酒石酸盐被转化为相应的环氧苷，并引入异丁基来获得关键的中间体，海马司特前体。本文还尝试了将所得到的海马体片段与锌螯合剂进行耦合。