Synthesis of Isosteric Analogues of Nicotinamide Adenine Dinucleotide Containing C-Nucleotide of Nicotinamide or Picolinamide

Two isosteric analogues of nicotinamide adenine dinucleotide, C-NAD (11) and C-PAD (12), in which the nicotinamide riboside portion is replaced by a C-nucleoside, were synthesized from 5-(β-d-ribofuranosyl)nicotinamide (7) and 6-(β-d-ribofuranosyl)picolinamide (8), respectively. Nucleoside 7 was prepared from the 2,3-O-isopropylidene-5-O-(tetrahydropyranyl)-d-ribonolactone (13) and 3-cyano-5-lithiopyridine as reported earlier. Nucleoside 8 was obtained by conversion of the bromo function of the 6-(2,3:4,5-di-O-isopropylidene-d-altro-pentitol-1-yl)-2-bromopyridine (14) into a carboxamido group followed by mesylation of the anomeric hydroxyl group to give derivative 18. Treatment of 18 with CF₃COOH/CHCl₃ caused deisopropylidenation with simultaneous cyclization into the desired 6-(β-d-ribofuranosyl)picolinamide (8). NAD analogues, C-NAD (11) and C-PAD (12), were synthesized by imidazole-catalyzed coupling of the corresponding 5′-monophosphates of 7 and 8 with the adenosine-5′-monophosphate. Dinucleotide 11 was found to inhibit the proliferation of L1210 cells (IC₅₀ = 7 µM) and to be a good competitive inhibitor of inosine monophosphate dehydrogenase (IMPDH, ID₅₀ = 20 µM) as well as bovine glutamate dehydrogenase (GDH, K_i = 15 µM). Interestingly, C-NAD (11) caused extremely potent noncompetitive inhibition of horse liver alcohol dehydrogenase (ADH, K_i = 1.1 nM), whereas C-PAD (12) was found to be a much less potent competitive inhibitor (K_i = 20 µM) of ADH.