Assembly of complimentary naphthyl units in nucleotidomimetic foldamers

Ikkanda, Brian Aki
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The large and complex architectures found in biomolecules not only are an amazing feat of molecular construction, but they also function to carry out all the processes necessary to sustain a living organism. For the organic chemist and biochemist that wish to mimic, improve or modify the structure and function of such natural molecular architectures, an understanding of non-covalent interactions in solution is necessary. In order to probe the particular inter- and intramolecular interactions involved in constructing higher order molecular architectures, the study of foldamers, small synthetic oligomers that adopt well-defined conformations in solution, has emerged. Our lab has been studying the particular interaction between complementary aromatic units, 1,4,5,8-naphthalenetetracarboxylic acid diimide (NDI) and 1,5-dialkoxynaphthalene (DAN) and their ability to drive the construction of aromatic foldamers in aqueous environments. Utilizing flexible peptide linked units of DAN and NDI, our lab has constructed a variety of unique folding assemblies. From the very first aromatic foldamer that folds into a pleated secondary structure in water to a heteroduplex system assembling oligo-DAN and oligo-NDI units in an intertwined fashion, the use of these complementary aromatic units has proven its versatility in foldamer assembly. Generally, this dissertation describes studies of the first NDI and DAN deoxyribonucleic acid oligonucleotides. While our previous foldamer assemblies utilized peptide linkers to string together DAN and NDI units, the work described herein draws inspiration from the sugar-phosphate backbone of DNA to assemble aromatic units. Chapter 2 describes the design and synthesis of 4,4’-dimethoxytrityl protected DAN and NDI phosphoramidites that can subsequently be incorporated into strands of natural DNA oligonucleotides using automated solid phase oligonucleotide synthesis. Chapter 3 investigates the insertion of a 3 base pair region of varying sequences of DAN and NDI into a 12-mer DNA oligonucleotide to explore the effect of DAN and NDI on duplex structure and stability. Chapter 4 describes the stability and structure of a 9-mer DNA oligonucleotide that incorporates two NDI-DAN-NDI triplet sequences either inserted into the interior of the duplex or appended at the terminal positions of the duplex. The NDI-DAN-NDI triplets appended to the terminal positions led to a profound increase in duplex stability (in comparison to internal positions), significantly beyond that seen with analogous sequences of G-C base pairs.