Oligonucleotide Analogues with Integrated Bases and Backbone. Part 22

Abstract

AbstractThe tritylated and silylated self‐complementary A*[s]U*[s]A*[s]U* and U*[s]A*[s]U*[s]A* tetramers 18 and 24, linked by thiomethylene groups (abbreviated as [s]) between a nucleobase and C(5′) of the neighbouring nucleoside unit were prepared by a linear synthesis based on S‐alkylation of 5′‐thionucleosides by 6‐(chloromethyl)uridines, 7 or 10, or 8‐(chloromethyl)adenosines, 12 or 15. The tetramers 18 and 24 were detritylated to the monoalcohols 19 and 25, and these were desilylated to the diols 20 and 26, respectively. The association of the tetramers 18–21 and 24–26 in CDCl3 or in CDCl3/(D6)DMSO 95 : 5 was investigated by the concentration dependence of the chemical shifts for HN(3) or H2NC(6). The formation of cyclic duplexes connected by four base pairs is favoured by the presence of one and especially of two OH groups. The diol 20 with the AUAU sequence prefers reverse‐Hoogsteen, and diol 26 with the UAUA sequence Watson–Crick base pairing. The structure of the cyclic duplex of 26 in CDCl3 at 2° was derived by a combination of AMBER* modeling and simulated annealing with NMR‐derived distance and torsion‐angle restraints resulting in a Watson–Crick base‐paired right‐handed antiparallel helix showing large roll angles, especially between the centre base pairs, leading to a bent helix axis.