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-(beta-D-ribofuranosyl)nicotinamide (7) and 6-(beta-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-bromopyrid ine (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-(beta-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 microM) and to be a good competitive inhibitor of inosine monophosphate dehydrogenase (IMPDH, ID50 = 20 microM) as well as bovine glutamate dehydrogenase (GDH, Ki = 15 microM). Interestingly, C-NAD (11) caused extremely potent noncompetitive inhibition of horse liver alcohol dehydrogenase (ADH, Ki = 1.1 nM), whereas C-PAD (12) was found to be a much less potent competitive inhibitor (Ki = 20 microM) of ADH.
Pankiewicz
K W
KW
Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, Cornell University, New York, New York 10021.
Zeidler
J
J
Ciszewski
L A
LA
Bell
J E
JE
Goldstein
B M
BM
Jayaram
H N
HN
Watanabe
K A
KA
D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000138:chemical synthesis* / Q000494:pharmacology*; D002417:Cattle; D005969:Glutamate Dehydrogenase / Q000037:antagonists & inhibitors; D006736:Horses; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D007939:Leukemia L1210 / Q000188:drug therapy / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D051379:Mice; D009243:NAD / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000737:chemistry; D010848:Picolinic Acids / Q000737:chemistry*; D012263:Ribonucleosides / Q000737:chemistry*
D000964:Antimetabolites, Antineoplastic; D010848:Picolinic Acids; D012263:Ribonucleosides; D009243:NAD; C052349:5-ribofuranosylnicotinamide; C057019:6-(beta-ribofuranosyl)picolinamide; D009536:Niacinamide; D000426:Alcohol Dehydrogenase; D007168:IMP Dehydrogenase; D005969:Glutamate Dehydrogenase