THE DEVELOPMENT OF ARTIFICIAL GENE REGULATION MOLECULES BASED ON CHEMICAL BIOLOGY

在本研究中，主要进行了以下三个项目。1)研制了具有蒽和脱氧氨基糖杂化结构的新型DNA光裂解剂。因此，我们发现以蒽和脱氧氨基糖分别作为DNA插层剂和DNA凹槽粘合剂的新型杂交体，在不添加任何添加剂的情况下，在长波紫外光照射下选择性地在鸟嘌呤位点切割双链DNA。此外，这些药物在光照射下对癌细胞表现出很强的细胞毒性。2)开发了新型凸起DNA识别分子。因此，设计的含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，并且发现杂合体选择性地识别和稳定g -凸起DNA，而互补DNA和A-，C-和t -凸起DNA不被杂合体识别。这些结果清楚地表明，所设计的杂交对检测g -凸起DNA是非常有用的。3)新型端粒酶抑制剂的开发。因此，基于溴化乙锭与DNA的g -四重奏结构相互作用并表现出端粒酶抑制活性的结构，设计和合成了几种衍生物。研究发现，溴化乙锭的C3和C8位氨基以及N-5位的四分化是其抑制端粒酶活性的必要条件。结果表明，甲基对端粒酶的抑制作用优于甲基对端粒酶的抑制作用。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。

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.