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THE DEVELOPMENT OF ARTIFICIAL GENE REGULATION MOLECULES BASED ON CHEMICAL BIOLOGY

基于化学生物学的人工基因调控分子的开发

基本信息

批准号：
15510180
负责人：
TOSHIMA Kazunobu
金额：
$ 2.37万
依托单位：
KEIO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

项目摘要

In this study, the following three main projects were carried out. 1)Novel DNA photocleaving agents possessing a hybrid structure of anthracene and deoxyamino sugar were developed. Thus, it was found that novel designed hybrids having anthracene and deoxyamino sugar as a DNA intercalator and a DNA groove binder, respectively, selectively cleaved double stranded DNA at the guanine site under the photoirradiation using a long wave-length UV without any additives. Furthermore, these agents were found to show strong cytotoxicity against cancer cells under the photoirradiation. 2)Novel bulge DNA recognition molecules were developed. Thus, the designed hybrid possessing cytosine and carbohydrate was synthesized via an effective glycosidation reaction, and found to selectively recognize and stabilize G-bulged DNA while complementally DNA and A-,C- and T-bulged DNAs were not recognized by the hybrid. These results clearly showed that the designed hybrid was very useful for detecting the G-bulged DNA. 3)Novel telomerase inhibitors were also developed. Thus, several derivatives were designed and synthesized based on the structure of ethidium bromide which was known to interact with G-quartet structure of DNA and exhibit telomerase inhibiting activity. It was found that the amino groups at the C3 and C8 positions and the quarternarization of the N-5 position of ethidium bromide were essential for its telomerase inhibiting activity. Furthermore, it was demonstrated that methyl group is more effective than ethyl group at the N-5 position of ethidium bromide for its telomerase inhibiting activity. These results gave significant information for designing novel telomerase inhibitors based on ethidium bromide structure.

在这项研究中，进行了以下三个主要项目。1)本文报道了一种新型的具有蒽和脱氧氨基糖杂化结构的DNA光切割剂。因此，发现分别具有蒽和脱氧氨基糖作为DNA嵌入剂和DNA沟结合剂的新设计的杂交体在使用长波长UV的光照射下在鸟嘌呤位点选择性地切割双链DNA，而不使用任何添加剂。此外，发现这些试剂在光照射下显示出对癌细胞的强细胞毒性。2)开发了新型的隆突DNA识别分子。因此，设计的具有胞嘧啶和碳水化合物的杂合体通过有效的糖苷化反应合成，并发现选择性地识别和稳定G-凸起的DNA，而互补DNA和A-，C-和T-凸起的DNA不被杂合体识别。这些结果清楚地表明，所设计的杂交是非常有用的检测G-凸起的DNA。3)还开发了新的端粒酶抑制剂。因此，基于溴化乙锭的结构，设计并合成了几种衍生物，已知溴化乙锭与DNA的G-四重结构相互作用并表现出端粒酶抑制活性。发现溴化乙锭C3和C8位的氨基和N-5位的季铵化是其抑制端粒酶活性所必需的。此外，证明溴化乙锭N-5位上的甲基比乙基更有效地抑制端粒酶活性。这些结果为设计基于溴化乙锭结构的新型端粒酶抑制剂提供了重要信息。