TOWARD CHEMICAL RIBONUCLEASES .2. SYNTHESIS AND CHARACTERIZATION OF NUCLEOSIDE-BIPYRIDINE CONJUGATES - HYDROLYTIC CLEAVAGE OF RNA BY THEIR COPPER(II) COMPLEXES

As part of our program to develop chemical ribonucleases that cleave RNA by phosphodiester hydrolysis, a systematic study of covalently linked nucleoside-2,2'pipyridine (bpy) conjungates is described. 2'-deoxythymidine was attached at both its 3'- and 5'-positions to bpy derivatives by using phosphoramidite chemistry, yielding after deprotection ammonium 2'-[4-(4'-methyl-2,2'-bipyridine-4-yl)butyl phosphate] (8) and triethylammonium 2'-deoxythymidine 5'-]4-]4'-methyl-2,2'-bipyridin-4-yl[butyl phosphate[ (11). 2'-Deoxyuridine was attached to a modified bpy via derivatization of the uracil ring at C-5, giving 5-]3-]]2-]]4-(4'-methyl-2,2'-bipyridin-4-yl)-1-oxobutyl[amino[ethyl[amino[-3-oxopropyl[-2'-deoxyuridine (16). These conjugates and the intermediate bpy derivatives were fully characterized by mass spectrometry and H-1, C-13, and P-31 NMR spectroscopy. The ability of the bpy moieties to bind (Cu(II) was demonstrated spectroscopically. The copper(II) complexes of 8, 11, and 16 were shown to hydrolyze RNA at 37-degrees-C and neutral pH. The difference in reactivity of 8, 11, and 16 provides the basis for optimizing the activity of hydrolytic chemical nucleases.