SYNTHESIS OF ISOSTERIC ANALOGS OF NICOTINAMIDE ADENINE-DINUCLEOTIDE CONTAINING C-NUCLEOTIDE OF NICOTINAMIDE OR PICOLINAMIDE

Two isosteric analogues of nicotinamide adenine dinucleotide, C-NAD (1 1) and C-PAD (12), in which the nicotinamide riboside portion is repla ced by a C-nucleoside, were synthesized from 5-(beta-D-ribofuranosyl)n icotinamide (7) and 6-(beta-D-ribofuranosyl)picolinamide (8), respecti vely. Nucleoside 7 was prepared from the ropylidene-5-O-(tetrahydropyr anyl)-D-ribonolactone (13) and 3-cyano-5-lithiopyridine as reported ea rlier. Nucleoside 8 was obtained by conversion of the bromo function o f the propylidene-D-altro-pentitol-1-yl)-2-bromopyridine (14) into a c arboxamido group followed by mesylation of the anomeric hydroxyl group to give derivative 18. Treatment of 18 with CF3COOH/CHCl3 caused deis opropylidenation with simultaneous cyclization into the desired 6-(bet a-D-ribofuranosyl)picolinamide (8). NAD analogues, C-NAD (11) and C-PA D (12), were synthesized by imidazole-catalyzed coupling of the corres ponding 5'-monophosphates of 7 and 8 with the adenosine-5'-monophospha te. Dinucleotide 11 was found to inhibit the proliferation of L1210 ce lls (IC50 = 7 muM) and to be a good competitive inhibitor of inosine m onophosphate dehydrogenase (IMPDH, ID50 = 20 muM) as well as bovine gl utamate dehydrogenase (GDH, K(i) = 15 muM). Interestingly, C-NAD (11) caused extremely potent noncompetitive inhibition of horse liver alcoh ol dehydrogenase (ADH, K(i) = 1.1 nM), whereas C-PAD (12) was found to be a much less potent competitive inhibitor (K(i) = 20 muM) of ADH.