NAD-based inhibitors with anticancer potential

Krzysztof Felczak; Robert Vince; Krzysztof W Pankiewicz

doi:10.1016/j.bmcl.2013.11.005

NAD-based inhibitors with anticancer potential

Bioorg Med Chem Lett. 2014 Jan 1;24(1):332-6. doi: 10.1016/j.bmcl.2013.11.005. Epub 2013 Nov 14.

Authors

Krzysztof Felczak¹, Robert Vince¹, Krzysztof W Pankiewicz²

Affiliations

¹ Center for Drug Design, University of Minnesota, 516 Delaware Street S.E., Minneapolis, MN 55455, USA.
² Center for Drug Design, University of Minnesota, 516 Delaware Street S.E., Minneapolis, MN 55455, USA. Electronic address: panki001@umn.edu.

PMID: 24269162
DOI: 10.1016/j.bmcl.2013.11.005

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.

Keywords: Inosine monophosphate dehydrogenase; Mycophenolic acid; Mycophenolic adenine dinucleotides; Nicotinamide adenine dinucleotide; Novel IMPDH inhibitors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
HT29 Cells
HeLa Cells
Humans
IMP Dehydrogenase / antagonists & inhibitors
IMP Dehydrogenase / metabolism
K562 Cells
Models, Molecular
Molecular Structure
NAD / analogs & derivatives
NAD / chemistry
NAD / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Enzyme Inhibitors
NAD
IMP Dehydrogenase
IMPDH1 protein, human
IMPDH2 protein, human