Chemical synthesis of benzamide adenine dinucleotide: inhibition of inosine monophosphate dehydrogenase (types I and II).
Treatment of 3-(2,3-O-isopropylidene-beta-D-ribofuranosyl)benzamide (6) with POCl3 in (EtO)3-PO afforded only little phosphorylation product (8, 5%), but the major product was 5'-chlorobenzamide riboside (7, 85%). Reaction of 6 with 2-cyanoethyl N,N-diisopropylchlorophosphoramidite followed by 2-cyanoethanol/tetrazole treatment and oxidation with tert-butyl peroxide gave a 1:1 mixture of the desired 5'-O-bis(2-cyanoethyl) phosphate 9 and the chloro derivative 7. This mixture was treated with methanolic ammonia and partitioned between CHCl3 and water. The 2',3'-O-isopropylidenebenzamide mononucleotide (8) was obtained in 21.2% overall yield from the aqueous layer. Compound 8 was then converted into the corresponding imidazolide 11b which, upon coupling with 2',3'-O-acetonide of AMP, afforded the acetonide of benzamide adenine dinucleotide (15) in 94% yield together with small amounts of symmetrical pyrophosphates P1,P2-bis(2',3'-O-isopropylideneadenosin-5'-yl)pyrophosphate (13, 3%) and P1,P2-bis(2',3'-O-isopropylidene-3-(carbamoylphenyl)-5'-ribosyl)py rophosphate (14, 2%). Deprotection of 15 with Dowex 50/H+ in water afforded the desired benzamide adenine dinucleotide (BAD) in 93% yield. BAD inhibits inosine monophosphate dehydrogenase type I (IC50 = 0.78 microM) and type II (IC50 = 0.88 microM) with same degree of potency.
Zatorski
A
A
OncorPharm, Inc., Gaithersburg, Maryland 20877, USA.
Watanabe
K A
KA
Carr
S F
SF
Goldstein
B M
BM
Pankiewicz
K W
KW
D000227:Adenine Nucleotides / Q000138:chemical synthesis* / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000138:chemical synthesis* / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
D000227:Adenine Nucleotides; D000964:Antimetabolites, Antineoplastic; D001549:Benzamides; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009363:Neoplasm Proteins; C100366:benzamide adenine nucleotide; C038167:thiazole-4-carboxamide adenine dinucleotide; D007168:IMP Dehydrogenase