title: NAD-based inhibitors with anticancer potential.
abstract: Three classes of novel inhibitors of inosine monophosphate dehydrogenase have been prepared and their anti-proliferative properties were evaluated against several cancer cell lines. (1) Mycophenolic adenine dinucleotide analogues (8-13) containing a substituent at the C2 of adenine ring were found to be potent inhibitors of IMPDH (Ki's in range of 0.6-82nM) and sub-μM inhibitors of leukemic K562 cell proliferation. (2) Mycophenolic adenosine (d and l) esters (20 and 21) showed a potent inhibition of IMPDH2 (Ki=102 and Ki=231nM, respectively) and inhibition of K562 cell growth (IC50=0.5 and IC50=1.6μM). These compounds serve both as inhibitors of the enzyme and as a depot form of mycophenolic acid. The corresponding amide analogue 22, also a potent inhibitor of IMPDH (Ki=84nM), did not inhibit cancer cell proliferation. (3) Mycophenolic-(l)- and (d)-valine adenine di-amide derivatives 25 (Ki=9nM) and 28 (Ki=3nM) were found to be very potent enzymatically, but did not inhibit proliferation of cancer cells.
authors.affiliation: Center for Drug Design, University of Minnesota, 516 Delaware Street S.E., Minneapolis, MN 55455, USA.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Felczak
authors.affiliation: Center for Drug Design, University of Minnesota, 516 Delaware Street S.E., Minneapolis, MN 55455, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Vince
authors.affiliation: Center for Drug Design, University of Minnesota, 516 Delaware Street S.E., Minneapolis, MN 55455, USA. Electronic address: panki001@umn.edu.
authors.forename: Krzysztof W
authors.initials: KW
authors.lastname: Pankiewicz
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D020014:K562 Cells; D008958:Models, Molecular; D015394:Molecular Structure; D009243:NAD / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009243:NAD; D007168:IMP Dehydrogenase; C488211:IMPDH1 protein, human; C501687:IMPDH2 protein, human
keywords: Inosine monophosphate dehydrogenase; Mycophenolic acid; Mycophenolic adenine dinucleotides; Nicotinamide adenine dinucleotide; Novel IMPDH inhibitors