title: Novel mycophenolic adenine bis(phosphonate) analogues as potential differentiation agents against human leukemia.
abstract: Novel mycophenolic adenine dinucleotide (MAD) analogues have been prepared as potential inhibitors of inosine monophosphate dehydrogenase (IMPDH). MAD analogues resemble nicotinamide adenine dinucleotide binding at the cofactor binding domain of IMPDH; however, they cannot participate in hydride transfer and therefore inhibit the enzyme. The methylenebis(phosphonate) analogues C2-MAD and C4-MAD were obtained by coupling 2',3'-O-isopropylideneadenosine 5'-methylenebis(phosphonate) (22) with mycophenolic alcohols 20 and 21 in the presence of diisopropylcarbodiimide followed by deprotection. C2-MAD was also prepared by coupling of mycophenolic methylenebis(phosphonate) derivative 30 with 2',3'-O-isopropylideneadenosine. Compound 30 was conveniently synthesized by the treatment of benzyl-protected mycophenolic alcohol 27 with a commercially available methylenebis(phosphonic dichloride) under Yoshikawa's reaction conditions. C2-MAD and C4-MAD were found to inhibit the growth of K562 cells (IC(50) = 0.7 microM and IC(50) = 0.1 microM, respectively) as potently as mycophenolic acid (IC(50) = 0.3 microM). In addition, C2-MAD and C4-MAD triggered vigorous differentiation of K562 cells an order of magnitude more potently than tiazofurin, and MAD analogues were resistant to glucuronidation in vitro. These results show that C2-MAD and C4-MAD may be of therapeutic interest in the treatment of human leukemias.
authors.affiliation: Pharmasset Inc., 1860 Montreal Road, Tucker, Georgia 30084, USA. kpankiewicz@pharmasset.com
authors.forename: Krzysztof W
authors.initials: KW
authors.lastname: Pankiewicz
authors.forename: Krystyna B
authors.initials: KB
authors.lastname: Lesiak-Watanabe
authors.forename: Kyoichi A
authors.initials: KA
authors.lastname: Watanabe
authors.forename: Steven E
authors.initials: SE
authors.lastname: Patterson
authors.forename: Hiremagalur N
authors.initials: HN
authors.lastname: Jayaram
authors.forename: Joel A
authors.initials: JA
authors.lastname: Yalowitz
authors.forename: Michael D
authors.initials: MD
authors.lastname: Miller
authors.forename: Michael
authors.initials: M
authors.lastname: Seidman
authors.forename: Alokes
authors.initials: A
authors.lastname: Majumdar
authors.forename: Gerd
authors.initials: G
authors.lastname: Prehna
authors.forename: Barry M
authors.initials: BM
authors.lastname: Goldstein
mesh_terms: D000227:Adenine Nucleotides; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D004164:Diphosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D020014:K562 Cells; D007938:Leukemia; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000227:Adenine Nucleotides; D000970:Antineoplastic Agents; D004164:Diphosphonates; D004791:Enzyme Inhibitors; D007527:Isoenzymes; C110804:mycophenolic adenine dinucleotide; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid