A new GC Binder for sequence-selective DNA recognition

This work mainly focuses on the synthesis of pyrrolo[2,3 b]pyridones as part of a larger modular system of heterocyclic ligands that are designed to bind DNA in a sequence-selective manner in the major groove. It is the first reported synthesis of such a scaffold. This biarylic system has been designed to form a triplex with a GC base pair forming three simultaneous hydrogen bonds. Extensive molecular modeling was done leading to an optimized design of a modular system with perfect complementarity to the Hoogsteen site inside DNA’s major groove. Flexible synthetic access to this binding motif consisting of a pyridone connected to a fused pyrrolo[2,3-b]pyridone, is presented. A wide range of functional elements have been introduced by minor modifications of the synthetic strategy. These functionalizations are necessary for two important purposes. For DNA recognition, the base pair binder was modified (Type I) in such a way that it can be attached to a DNA-compatible backbone with self-repeating units. In this regard, a short C2 spacer was introduced at the 5- position of the pyrrolopyridone nucleus. For the correct hydrogen bonding capability to be established, the base triplet formation with an isolated GC base pair must be proven. In the absence of the powerful π-stacking contributions, this must be done in highly nonpolar solvents because polar solvents (even DMSO) will strongly interfere with the three new weak hydrogen bonds. This is a major drawback in the design of all artificial base pair binders; even pyrrolo[2,3-b]pyridone scaffold is not soluble enough in CDCl3 due to the presence of both pyridone amides. Without disturbing the hydrogen bonding recognition site of the binder, a modification (Type II) was envisaged on the back of the pyrrole ring. Solubilizing nonpolar substituents were installed on 3- position of the nucleus. These derivatives were conveniently prepared by introducing minor changes in the established synthetic route.



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