TY - JOUR
T1 - Selective inhibition of nicotinamide adenine dinucleotide kinases by dinucleoside disulfide mimics of nicotinamide adenine dinucleotide analogues
AU - Petrelli, Riccardo
AU - Sham, Yuk Yin
AU - Chen, Liqiang
AU - Felczak, Krzysztof
AU - Bennett, Eric
AU - Wilson, Daniel
AU - Aldrich, Courtney
AU - Yu, Jose S.
AU - Cappellacci, Loredana
AU - Franchetti, Palmarisa
AU - Grifantini, Mario
AU - Mazzola, Francesca
AU - Di Stefano, Michele
AU - Magni, Giulio
AU - Pankiewicz, Krzysztof W.
N1 - Funding Information:
These studies were funded by the Center for Drug Design, University of Minnesota.
PY - 2009/8/1
Y1 - 2009/8/1
N2 - Diadenosine disulfide (5) was reported to inhibit NAD kinase from Lysteria monocytogenes and the crystal structure of the enzyme-inhibitor complex has been solved. We have synthesized tiazofurin adenosine disulfide (4) and the disulfide 5, and found that these compounds were moderate inhibitors of human NAD kinase (IC50 = 110 μM and IC50 = 87 μM, respectively) and Mycobacterium tuberculosis NAD kinase (IC50 = 80 μM and IC50 = 45 μM, respectively). We also found that NAD mimics with a short disulfide (-S-S-) moiety were able to bind in the folded (compact) conformation but not in the common extended conformation, which requires the presence of a longer pyrophosphate (-O-P-O-P-O-) linkage. Since majority of NAD-dependent enzymes bind NAD in the extended conformation, selective inhibition of NAD kinases by disulfide analogues has been observed. Introduction of bromine at the C8 of the adenine ring restricted the adenosine moiety of diadenosine disulfides to the syn conformation making it even more compact. The 8-bromoadenosine adenosine disulfide (14) and its di(8-bromoadenosine) analogue (15) were found to be the most potent inhibitors of human (IC50 = 6 μM) and mycobacterium NAD kinase (IC50 = 14-19 μΜ reported so far. None of the disulfide analogues showed inhibition of lactate-, and inosine monophosphate-dehydrogenase (IMPDH), enzymes that bind NAD in the extended conformation.
AB - Diadenosine disulfide (5) was reported to inhibit NAD kinase from Lysteria monocytogenes and the crystal structure of the enzyme-inhibitor complex has been solved. We have synthesized tiazofurin adenosine disulfide (4) and the disulfide 5, and found that these compounds were moderate inhibitors of human NAD kinase (IC50 = 110 μM and IC50 = 87 μM, respectively) and Mycobacterium tuberculosis NAD kinase (IC50 = 80 μM and IC50 = 45 μM, respectively). We also found that NAD mimics with a short disulfide (-S-S-) moiety were able to bind in the folded (compact) conformation but not in the common extended conformation, which requires the presence of a longer pyrophosphate (-O-P-O-P-O-) linkage. Since majority of NAD-dependent enzymes bind NAD in the extended conformation, selective inhibition of NAD kinases by disulfide analogues has been observed. Introduction of bromine at the C8 of the adenine ring restricted the adenosine moiety of diadenosine disulfides to the syn conformation making it even more compact. The 8-bromoadenosine adenosine disulfide (14) and its di(8-bromoadenosine) analogue (15) were found to be the most potent inhibitors of human (IC50 = 6 μM) and mycobacterium NAD kinase (IC50 = 14-19 μΜ reported so far. None of the disulfide analogues showed inhibition of lactate-, and inosine monophosphate-dehydrogenase (IMPDH), enzymes that bind NAD in the extended conformation.
KW - Dithioadenosine analogues, NAD conformation
KW - Enzyme inhibition
KW - NAD kinase
KW - NADP
KW - Tiazofurin
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U2 - 10.1016/j.bmc.2009.06.013
DO - 10.1016/j.bmc.2009.06.013
M3 - Article
C2 - 19596199
AN - SCOPUS:67651102849
SN - 0968-0896
VL - 17
SP - 5656
EP - 5664
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 15
ER -
