title: The practical synthesis of a methylenebisphosphonate analogue of benzamide adenine dinucleotide: inhibition of human inosine monophosphate dehydrogenase (type I and II).
abstract: beta-Methylene-BAD (8), a nonhydrolyzable analogue of benzamide adenine dinucleotide (BAD), was synthesized as potential inhibitor of human inosine monophosphate dehydrogenase (IMPDH). Treatment of 2',3'-O-isopropylideneadenosine 5'-methylenebisphosphonate (15) with DCC afforded P1,P4-bis(2',3'-O-isopropylideneadenosine) 5'-P1,P2:P3,P4-dimethylenetetrakisphosphonate (17). This compound was further converted with DCC to an active intermediate 18 which upon reaction with 3-(2',3'-O-isopropylidene-beta-D-ribofuranosyl)benzamide (19) gave, after hydrolysis and deisopropylidenation, the desired beta-methylene-BAD (8) in 95% yield. In a similar manner, treatment of 18 with 2',3'-O-isopropylidenetiazofurin (21) followed by hydrolysis and deprotection afforded beta-methylene-TAD (5) in 91% yield. Compound 8 (IC50 = 0.665 microM) was found to be a 6-8 times less potent inhibitor of IMPDH than 5 (IC50 = 0.107 microM) and was almost equally potent against IMPDH type I and type II. Although TAD and beta-methylene-TAD were bound by LADH with the same affinity, the binding affinity of 8 toward LADH (Ki = 333 microM) was found to be 50-fold lower than that of the parent pyrophosphate 7 (Ki = 6.3 microM).
authors.affiliation: Codon Pharmaceuticals, Inc., Gaithersburg, Maryland 20877, USA.
authors.forename: K W
authors.initials: KW
authors.lastname: Pankiewicz
authors.forename: K
authors.initials: K
authors.lastname: Lesiak
authors.forename: A
authors.initials: A
authors.lastname: Zatorski
authors.forename: B M
authors.initials: BM
authors.lastname: Goldstein
authors.forename: S F
authors.initials: SF
authors.lastname: Carr
authors.forename: M
authors.initials: M
authors.lastname: Sochacki
authors.forename: A
authors.initials: A
authors.lastname: Majumdar
authors.forename: M
authors.initials: M
authors.lastname: Seidman
authors.forename: K A
authors.initials: KA
authors.lastname: Watanabe
mesh_terms: D000227:Adenine Nucleotides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006736:Horses; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D014407:Tumor Cells, Cultured
chemical_list: D000227:Adenine Nucleotides; D000964:Antimetabolites, Antineoplastic; D001549:Benzamides; D004791:Enzyme Inhibitors; D007527:Isoenzymes; C100366:benzamide adenine nucleotide; D000426:Alcohol Dehydrogenase; D007168:IMP Dehydrogenase