PYRIMIDINE NUCLEOSIDES AND THEIR 5'-AMINO-5'-DEOXYANALOGS MODIFIED WITH 3-INDOLEPROPIONIC, NICOTINIC, AND 1-NITROANTHRAQUINON-2-CARBOXYLIC ACIDS

The reaction of 5'-amino-2',5'-dideoxyuridine and 5'-amino-5'-deoxy-2',3'-O-ethoxymethyliden-6-azauridine with 3-(3-indolyl)propionic or 1-nitroanthraquinon-2-carboxylic acids in THF in the presence of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) resulted in the corresponding amide derivatives. The reaction conditions of the standard procedure for the removal of the O-alkylidene protecting group turned out to be too severe for the 5'-N-acylamide derivatives of 6-azauridine. 5'-Deoxy-5'-[3-(3-indolyl)propionylamino]-6-azauridine was synthesized from 5'-amino-5'-deoxy-6-azauridine and 3-(3-indolyl)propionic acid in THF in the presence of EEDQ. A reaction between 5'-O-tosyl-2',3'-O-ethoxymethyliden-6-azauridine and 3-aminopropanol gave 3-(3-hydroxypropylamino)-2-(2',3'-O-ethoxymethylidene-beta-D-ribofuranosyl)-as-triazine-5(2H)-one, the structure of which was confirmed also by synthesis from O-2,5'-anhydronucleoside and 3-aminopropanol followed by further chemical transformations. A reaction of 3-(3-hydroxypropylamino) derivative obtained with nicotinoyl chloride prepared in situ, or with 1-nirtoanthraquinon-2-carboxylic acid in the presence of DCC with subsequent deprotection, afforded 3-[(3-pyridin-3-ylcarboxy)propylamino]- or 3-[3-(1-nitroanthraquinon-2-carboxy)propylamino]-2-beta-D-ribofuranosyl-as-triazine-5(2H)-one, respectively. Structures of the nucleosides prepared were examined by H-1 NMR spectroscopy. 2',5'-Dideoxy-5'-[(1-nitroanthraquinon-2-carbonyl)amino]uridine at a 10(-4) M concentration was shown to inhibit thymidine incorporation into cell DNA (CE(50) 10(-5) M) by 72%.