Research Project
3498631
In this Phase I study we will improve the efficiency and develop the linking chemistry of a novel class of DNA cleavage reagents. These agents, which undergo thermally triggered radical formation will be modified with an intercalating group in order to increase the efficiency of DNA cleavage. The thermal cleavers can be prepared using well established synthetic routes which provide ready access to a wide variety of derivatives. The length of the linker arm between the intercalator and the cleaver will be one structural variable examine. These compounds will be tested as footprinting agents, useful tools in molecular biology relevant to the study of molecular recognition. Sequence specificity and efficiency of cleavage will be examined under a variety of temperatures and reaction conditions. Base sequence specificity will vary according to the nature of the acridine intercalator chosen. The effect of linker arm length on efficiency of cleavage will be optimized with the aid of computer assisted molecular design. Another aim of this Phase I study is to prepare thermally triggered cleavage agents with electrophilic groups capable of reaction with nucleophilic oligonucleotides. The reaction of these highly reactive compounds with model nucleophilic will be examined. These experiments constitute a feasibility study for the development of the thermally triggered cleavage agents as oligonucleotide targeted affinity cleavage agents (Phase II). Such sequence specific DNA cleaving agents should be especially effective as antisense inhibitors of gene expression and, as such, have utility as anticancer or anti-infective drugs.
