STUDY OF INTERACTION BETWEEN DNA AND ANTIBIOTICS

主要目的是阐明相互作用的原理。 在DNA和抗生素之间。这将通过确定和 分析寡核苷酸-抗生素复合体的晶体结构， 此外，寡核苷酸和化学上的络合物 改良型抗生素，包括非活性抗生素。最后，我们将总结一下 结构确定的结果，我们将使用 获得的信息试图预测适当的化学修饰 抗生素，以提高其生物活性，特别是 抗肿瘤活性。作为第一个项目，我们将拿起阿霉素和 柔红霉素，属于蒽环类抗生素家族。他们 目前被用作最有效的治疗药物 治疗某些白血病和/或实体瘤患者。 阿霉素在C-13和/或C-14上的衍生化产生了几个 生物活性和非活性类似物。为了检查准确的 C-13和/或C-14侧链的生物和物理作用 抗生素，我们将结晶并确定其晶体结构 部分寡核苷酸与蒽环类抗生素的络合物 包括它们的类似物，通过C-13和/或C-14的衍生化形成。 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)。 在此授权期内，我们将致力于结晶和 寡核苷酸-抗生素复合体的X射线初步研究。我们 当我们获得合理的支持时，将申请未来对该项目的支持 本次调查的初步结果。

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.