STUDY OF INTERACTION BETWEEN DNA AND ANTIBIOTICS

主要目标是阐明相互作用的原则 DNA和抗生素之间的联系 这将通过确定和 分析了阿托西肽-抗生素复合物的晶体结构， 此外，寡核苷酸和化学上 改良的抗生素，包括无活性的抗生素。 最后，我们将总结 结构测定的结果，我们将使用 获得的信息，试图预测适当的化学修饰 抗生素，以增加其生物活性，特别是 抗肿瘤活性。 作为第一个项目，我们将拿起阿霉素， 柔红霉素，其属于蒽环类抗生素家族。 他们 目前被用作最有效的治疗剂， 治疗患有某些白血病和/或实体瘤的患者。 在多柔比星的C-13和/或C-14处的衍生化已经产生了几种 生物活性和非活性类似物。 为了检验 C-13和/或C-14侧链的生物和物理作用 抗生素，我们将结晶和确定晶体结构， 选择的寡核苷酸和蒽环类抗生素之间的复合物 包括它们的类似物，其通过在C-13和/或C-14处衍生化形成。 此外，结合这些抗生素的DNA序列效应将是 通过选择四种不同的寡核苷酸序列进行检查， d（GGCGCC）、d（GACGTC）、d（GTCGAC）和d（GCCGGC）。 在此资助期内，我们将集中精力， 初步的X射线研究的利福昔肽抗生素复合物。 我们 我们将申请未来的支持，当我们获得合理的 初步调查结果。

The primary goal is the elucidation of the principles of interaction between DNA and antibiotics. This will be accomplished by determining and analyzing the crystal structures of oligonucleotide-antibiotic complexes, and, in addition, the complexes between the oligonucleotide and chemically modified antibiotics including inactive ones. Finally, we will summarize the results of the structure determinations, and we will use the information gained to try to predict appropriate chemical modifications of the antibiotics to increase their biological activities, especially antitumor activity. As the first project, we will pick up doxorubicin and daunorubicin, which belong to the anthracycline antibiotic family. They are currently being used as the most effective therapeutic agents in the treatment of patients with certain leukemias and/or solid tumors. Derivatization at C-13 and/or C-14 of the doxorubicin have produced several biologically active and inactive analogues. In order to examine the exact biological and physical role of the C-13 and/or C-14 side chain of the antibiotic, we will crystallize and determine the crystal structures of complexes between selected oligonucleotides and anthracycline antibiotics including their analogues, formed by derivatization at C-13 and/or C-14. In addition, the DNA sequence effects of binding these antibiotics will be examined by selecting the four different sequences of oligonucleotides, d(GGCGCC), d(GACGTC), d(GTCGAC) and d(GCCGGC). In this grant period, we will focus our effort on the crystallization and preliminary X-ray studies of the oligonucleotide-antibiotic complexes. We will apply for future support for this project when we obtain reasonable preliminary results of this investigation.