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.
| Takusagawa, F (1990) The crystal structure of d(GTACGTAC) at 2.25 A resolution: are the A-DNA's always unwound approximately 10 degrees at the C-G steps? J Biomol Struct Dyn 7:795-809 |
