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Creation and efficient synthesis of nucleic acids and related compounds with valuable functionality and bioactivity

具有有价值的功能和生物活性的核酸和相关化合物的创建和有效合成

基本信息

批准号：
16350086
负责人：
HAYAKAWA Yoshihiro
金额：
$ 9.98万
依托单位：
Nagoya University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

项目摘要

(1) We developed a new strategy for the stereoselective preparation of dideoxyribonucleoside phosphorothioates with the (R) or the (S) configuration at the stereogenic phosphorus atom, and, based on this strategy, achieved the synthesis of oligodeoxyribonucleotides with stereochemically pure phosphate/phosphorothioate chimeric backbones, which are important compounds for antisense chemotherapy.(2) We developed new methods for the synthesis of c-di-GMP and its various analogs; these methods are capable of providing target compounds in large amounts, such as hundreds of milligrams to several grams. The synthesis allowed us to carry out extensive investigations of the biological activities of c-di-GMP and its analogs. As a result, we found that c-di-GMP appears to act as a second messenger in bacteria and shows a variety of important bioactivities. Among them, the particularly attractive one is the regulation of biofilm formation and infection to host cells by various bacteria; that is, inhibition of biofilm formation of S. aureus, P. aeruginosa and E. coli; reduction of infection of S. aureus to HeLa cells; reduction of the virulence of biofilm-forming S. aureus strains in a mouse model of mastitis infection in vivo; and activation of immune response. Further, it was disclosed that c-di-GMP inhibits basal and growth factor-stimulated human colon cancer cell proliferation.

(1)我们开发了一种立体选择性制备双脱氧核糖核苷硫代硫酸酯的新策略，并在此策略的基础上实现了具有立体化学纯的磷酸/硫代磷酸嵌合骨架的寡脱氧核苷酸的合成，这是反义化疗的重要化合物。(2)我们开发了合成c-二鸟苷及其各种类似物的新方法，这些方法能够提供大量的目标化合物，如数百毫克到几克。该合成使我们能够对c-di-GMP及其类似物的生物活性进行广泛的研究。结果，我们发现c-di-GMP似乎在细菌中扮演着第二信使的角色，并显示出多种重要的生物活性。其中特别吸引人的是各种细菌对生物膜形成和对宿主细胞感染的调节；即抑制金黄色葡萄球菌、铜绿假单胞菌和大肠杆菌的生物膜形成；减少金黄色葡萄球菌对HeLa细胞的感染；在小鼠乳房炎感染模型中降低形成生物膜的金黄色葡萄球菌菌株的毒力；以及激活免疫反应。此外，还揭示了c-di-GMP抑制基础和生长因子刺激的人结肠癌细胞的增殖。

项目成果

期刊论文数量（28）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pyrimido[4,5-d]pyrimidine-2,4,5,7-(1H,3H,6H,8H)-tetraone as a novel universal base.

嘧啶并[4,5-d]嘧啶-2,4,5,7-(1H,3H,6H,8H)-四酮作为新型通用碱基。

DOI：
发表时间：
2005
期刊：
Nucleic Acids Symp. Ser. 49
影响因子：
0
作者：
M.Kataoka;T.Hirano;K.Kuroda;Y.Hayakawa
通讯作者：
Y.Hayakawa

3′,5′-Cyclic diguanylic acid (c-di-GMP) inhibits basal and growth factor-stimulated human colon cancer cell proliferation

DOI：
10.1016/j.bbrc.2005.01.093
发表时间：
2005-04-01
期刊：
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
影响因子：
3.1
作者：
Karaolis, DKR;Cheng, KR;Raufman, JP
通讯作者：
Raufman, JP

Novel synthesis and characterization of bioconjugate block copolymers having oligonucleotides.

DOI：
10.1021/bm0502462
发表时间：
2005-06
期刊：
Biomacromolecules
影响因子：
6.2
作者：
Atsushi Noro;Yutaka Nagata;M. Tsukamoto;Y. Hayakawa;A. Takano;Y. Matsushita
通讯作者：
Atsushi Noro;Yutaka Nagata;M. Tsukamoto;Y. Hayakawa;A. Takano;Y. Matsushita

Frontiers in Organic Chemistry, Vol.1

有机化学前沿，第 1 卷