Isosteric analogues of nicotinamide adenine dinucleotide derived from furanfurin, thiophenfurin, and selenophenfurin as mammalian inosine monophosphate dehydrogenase (type I and II) inhibitors.
Dinucleotides TFAD (6), FFAD (7), and SFAD (8), isosteric NAD analogues derived, respectively, from C-nucleosides 5-beta-d-ribofuranosylthiophene-3-carboxamide (thiophenfurin, 1), 5-beta-d-ribofuranosylfuran-3-carboxamide (furanfurin, 2), and 5-beta-d-ribofuranosylselenophene-3-carboxamide (selenophenfurin, 5), were synthesized as human inosine monophosphate dehydrogenase (IMPDH) type I and II inhibitors. The synthesis was carried out by imidazole-catalyzed coupling of the 5'-monophosphate of 1, 2, and 5 with AMP. These dinucleotides, which are also analogues of thiazole-4-carboxamide adenine dinucleotide (TAD) and selenazole-4-carboxamide adenine dinucleotide (SAD), the active metabolites of the oncolytic C-nucleosides 2-beta-D-ribofuranosylthiazole-4-carboxamide (tiazofurin) and 2-beta-D-ribofuranosylselenazole-4-carboxamide (selenazofurin), were evaluated for their inhibitory potency against recombinant human IMPDH type I and II. The order of inhibitory potency found was SAD > SFAD = TFAD = TAD >> FFAD for both enzyme isoforms. No significant difference was found in inhibition of IMPDH type I and II.
Franchetti
P
P
Dipartimento di Scienze Chimiche, Università di Camerino, Via S. Agostino, 1, 62032 Camerino, Italy. grima@camserv.unicam.it
Cappellacci
L
L
Perlini
P
P
Jayaram
H N
HN
Butler
A
A
Schneider
B P
BP
Collart
F R
FR
Huberman
E
E
Grifantini
M
M
D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D007700:Kinetics; D009243:NAD / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016566:Organoselenium Compounds / Q000737:chemistry*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D012263:Ribonucleosides / Q000737:chemistry*
D004791:Enzyme Inhibitors; D016566:Organoselenium Compounds; D011994:Recombinant Proteins; D012263:Ribonucleosides; C095763:furanfurin; C106280:selenophenfurin; D009243:NAD; C095764:thiophenfurin; D007168:IMP Dehydrogenase