Conformational studies on 2',3'-unsaturated pentopyranosyl nucleosides by H-1 NMR spectroscopy. Impact of pi->sigma* interactions on the axial preference of the purine versus pyrimidine nucleobase

A variable-temperature H-1 NMR study on beta- and alpha-D-glycero-pent-2'-enopyranosyl nucleosides 1-10 has shown that the constituent pyranosyl moiety is involved in a rapid two-state H-6(5) reversible arrow E-5/S-5(4) conformational equilibrium. The results of the conformational analysis of (3)J(HH) coupling constants were compared with the trends of X-ray crystallography and ab initio calculations, which support the two-state dynamic equilibrium and suggest hat the equilibrium is affected by the nature of the heterocyclic aglycon. The beta nucleosides 1-5 adopt predominantly (approximately 95% in purine and 80% in pyrimidine nucleosides at 298 K) the conformation that is intermediate between the E-5 and S-5(4) canonical forms, where both the nucleobase and 4'-OH are in the axial orientation. The pyranosyl moiety of alpha-purine nucleosides 6 and 7 is involved in an unbiased two-state conformational equilibrium. On the other hand, the alpha-pyrimidine nucleosides 8-10 show a conformational bias of ca. 75% toward E-5 canonical form. The van't Hoff type analysis of the changes in the conformational equilibrium with temperature afforded thermodynamic data on H-6(5) reversible arrow E-5/S-5(4) conformational equilibrium in 1-10. The comparative analysis of Delta H degrees has shown that H-6(5) reversible arrow E-5/S-5(4) conformational equilibrium in 1-10 is driven by the fine tuning of O6'-Cl'-N1/9 anomeric effect, the gauche effect of the [O6'-C5'-C4'-O4'] fragment, the interaction between pi-system of the C2'-C3' bond with the heterocyclic aglycon and 4'-OH in the allylic position, and the intrinsic steric effect. Dissection of the individual contributions to the drive of conformational equilibrium of 1-10 has shown that the relative strength of pi(-->) sigma*(Cl'-N1/9) interactions in purine vs pyrimidine nucleobases increases in the following order: cytosine < uracil < thymine < adenine < ganine

Synthesis of triazolylmethyl-linked nucleoside analogs via combination of azidofuranoses with propargylated nucleobases and study on their cytotoxicity

KARAYILDIRIM, Tamer/0000-0001-7451-0810; HALAY, Erkan/0000-0002-0084-7709WOS: 000429350900009Copper(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition reactions (CuAAC) between azidofuranoses and propargyl-nucleobases were carried out in the presence of CuSO4 center dot 5H(2)O and sodium ascorbate as catalytic system to provide the corresponding 1,4-disubstituted-1,2,3-triazole-bridged nucleoside analogs in good yields. Twelve new sugar-based triazolylmethyl-linked nucleoside analogs were synthesized and screened for their cytotoxic activity against MDA-MB-231, Hep3B, PC-3, SH-SY5Y, and HCT-116 cancer cell lines and control cell line (L929). Most of the compounds were moderately effective against all the cancer cell lines assayed. Particularly, among the tested compounds, 1,2,3-triazole-linked 5-fluorouracil-mannofuranose hybrid was found to be the most potent cytotoxic agent against HCT-116, Hep3B, SH-SY5Y cells with IC50 values of 35.6, 71.1, and 75.6 mu M, respectively. None of the triazolylmethyl-linked nucleoside analogs exhibited cytotoxic effect against the control cells L929.TUBITAK-Research Council of Turkey [114Z757]; TUBITAK-BIDEBTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [2211A]This work was supported by TUBITAK-Research Council of Turkey with the project number 114Z757. Author E. Halay also offers his profound thanks to TUBITAK-BIDEB 2211A for their bursary support