Several neurological disorders result from the expansion of (CAG)n/(CTG)n trinucleotide repeat (TNR) microsatellite sequences in the human genome. As part of the expansion process, the formation of non-B DNA hairpin conformations has been proposed in the base excision repair mechanism, within which an oxidized guanine residue is excised by 7,8-dihydro-8-oxoguanine glycosylase and repaired by �-polymerase. At this stage, DNA slippage can occur, forming hairpin conformations and leading to the addition of extra bases in the sequence. We propose that developing small molecules that have high binding affinity to the CAG/CTG sequence can be used to �clamp� the DNA duplex, preventing such slippage. We have constructed a model DNA system with a (CAG)20/(CTG)20 unit in a 100-mer duplex, with an abasic site at the first 5'-CAG repeat site. This work focuses on the design and synthesis of naphthyridine/azaquinoline analogs and their potential to inhibit TNR expansion during the repair process.

Synthesis of naphthyridine/azaquinoline analogs for the disruption of TNR expansions in the base excision repair mechanism

245th National Meeting (2013)

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