The Practical Synthesis of a Methylenebisphosphonate Analogue of Benzamide Adenine Dinucleotide:  Inhibition of Human Inosine Monophosphate Dehydrogenase (Type I and II)

• Published in: Journal of medicinal chemistry 1997-04, Vol.40 (8), p.1287-1291
• Main Authors: Pankiewicz, Krzysztof W, Lesiak, Krystyna, Zatorski, Andrzej, Goldstein, Barry M, Carr, Stephen F, Sochacki, Marek, Majumdar, Alokes, Seidman, Michael, Watanabe, Kyoichi A
• Format: Article
• Language: English
• Subjects: Adenine Nucleotides - chemical synthesis; Adenine Nucleotides - chemistry; Adenine Nucleotides - pharmacology; Alcohol Dehydrogenase - antagonists & inhibitors; Animals; Antimetabolites, Antineoplastic - chemical synthesis; Antimetabolites, Antineoplastic - chemistry; Antimetabolites, Antineoplastic - pharmacology; Antineoplastic agents; Benzamides - chemical synthesis; Benzamides - chemistry; Benzamides - pharmacology; Biological and medical sciences; Chromatography, High Pressure Liquid; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; General aspects; Horses; Humans; IMP Dehydrogenase - antagonists & inhibitors; Isoenzymes - antagonists & inhibitors; Kinetics; Liver - enzymology; Medical sciences; Pharmacology. Drug treatments; Tumor Cells, Cultured
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm960641y

β-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 P 1,P 4-bis(2‘,3‘-O-isopropylideneadenosine) 5‘-P 1,P :P ,P -dimethylenetetrakisphosphonate (17). This compound was further converted with DCC to an active intermediate 18 which upon reaction with 3-(2‘,3‘-O-isopropylidene-β-d-ribofuranosyl)benzamide (19) gave, after hydrolysis and deisopropylidenation, the desired β-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 β-methylene-TAD (5) in 91% yield. Compound 8 (IC50 = 0.665 μM) was found to be a 6−8 times less potent inhibitor of IMPDH than 5 (IC50 = 0.107 μM) and was almost equally potent against IMPDH type I and type II. Although TAD and β-methylene-TAD were bound by LADH with the same affinity, the binding affinity of 8 toward LADH (K i = 333 μM) was found to be 50-fold lower than that of the parent pyrophosphate 7 (K i = 6.3 μM).