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Oligonucleotide Analogues with Integrated Bases and Backbone. Part 28: Hydrazide- and Amide-Linked Analogues. 2. Di-, Tetra-, Octa-, and Decamers: Synthesis and Association

The protected hydrazide-linked uracil- and adenine-derived tetranucleoside analogues 17, 19, and 21 were synthesized in solution by coupling the dimeric hydrazines 6 and 10 with the carboxylic acids 7, 11, and 16. These hydrazines and acids were obtained by partially deprotecting the hydrazines 5, 9, and 15, and these were prepared by coupling the hydrazines 3 and 14 with the carboxylic acids 4 and 8. The crystal structure analysis of the fully protected UU dimer 5 showed the formation of an antiparallel cyclic duplex with the uracil units H-bonded via HN(3) and OC(2). Stacking interactions were observed between the uracil units with a buckle twist of 30.9°, and between the uracil unit II and the fluoren-9-yl group of Fmoc (=9H-fluoren-9-yl)methoxycarbonyl). The hydrazide HN(3′) and the CO group of Fmoc form an intramolecular H-bond. The uracil- and adenine-derived, water-soluble hydrazide-linked self-complementary octamers 23–32 and the non-self-complementary uracil derived decamer 33 were obtained by coupling the carboxylic acids 4 and 8 on a solid support. 1H-NMR Analysis in CDCl3, mixtures of CDCl3 and (D6)DMSO, and (D8)THF showed that the partially deprotected dimers 5, 6, 12, and 13 form weakly associated linear duplexes. The partially deprotected tetramers 17 and 18 do not associate. The hydrazide-linked octamers 23–32 do not stack in aqueous solution, and the non-self-complementary decamer 33 does not stack with the complementary strands of DNA 43 and RNA 42. The Cbz-protected amide-linked octamers 51–56 derived from uracil, adenine, cytosine, and guanine were obtained as the main products by solid-phase synthesis from the carboxylic acids 46–49. The fully deprotected amide-linked octamers proved insoluble, and could neither be purified nor analysed.

oligonucleotides; X-ray crystallography; peptides; PNA Analogues; association

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