A series of 7-aryl- and 7-hetaryl-7-deazaadenosines was prepared by the cross-coupling reactions of unprotected or protected 7-iodo-7-deazaadenosines with (het)arylboronic acids, stannanes, or zinc halides. Nucleosides bearing 5-membered heterocycles at the position 7 exerted potent in vitro antiproliferative effects against a broad panel of hematological and solid tumor cell lines. Cell cycle analysis indicated profound inhibition of RNA synthesis and induction of apoptosis in treated cells. Intracellular conversion to triphosphates has been detected with active compounds. The triphosphate metabolites showed only a weak inhibitory effect on human RNA polymerase II, suggesting potentially other mechanisms for the inhibition of RNA synthesis and quick onset of apoptosis. Initial in vivo evaluation demonstrated an effect of 7-(2-thienyl)-7-deazaadenine ribonucleoside on the survival rate in syngeneic P388D1 mouse leukemia model.
Raman and Raman optical activity spectra of L- and D-proline zwitterionic (PROZW) forms were recorded for H(2)O and D(2)O solutions in a wide frequency range and analyzed with respect to the motion of the proline ring and rotation of the carbonyl group. The solution spectra were additionally compared to Raman scattering of glass and crystalline powder proline. Solution and glass spectral band broadenings are similar and reveal information about the extent of internal molecular motion. Two distinct but equally populated flexible forms were found in the glass and the solution. The equal population is consistent with NMR data, temperature, and concentration dependencies. The molecular flexibility is reduced significantly in the crystal, however, where only one conformer is present. Consequently, the crystal bands are narrow and exhibit minor frequency shifts. The spectra were interpreted with the aid of density functional theory computations involving both continuum and explicit solvent. A two-dimensional potential energy surface pertaining to the five-member ring puckering coordinates was constructed and used for dynamical averaging of spectral properties. Comparison of the computed and experimental bandwidths suggests that the puckering is strongly correlated with the carbonyl rotation. An averaging over these two motions produces similar results. The interpretation of the Raman experiments with the aid of the simulation techniques also indicates that the environment modulates properties of the hydrophobic part of the molecule indirectly by interacting with the ionic group. Such behavior may be important for the reactivity and biological activity of proline-containing peptides and proteins.
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