TY - JOUR
T1 - NAD-based inhibitors with anticancer potential
AU - Felczak, Krzysztof
AU - Vince, Robert
AU - Pankiewicz, Krzysztof W.
PY - 2014/1/1
Y1 - 2014/1/1
N2 - 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 0.6-82 nM) 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 = 231 nM, respectively) and inhibition of K562 cell growth (IC50 = 0.5 and IC50 = 1.6 μM). 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 = 84 nM), did not inhibit cancer cell proliferation. (3) Mycophenolic-(l)-and (d)-valine adenine di-amide derivatives 25 (Ki = 9 nM) and 28 (Ki = 3 nM) were found to be very potent enzymatically, but did not inhibit proliferation of cancer cells.
AB - 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 0.6-82 nM) 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 = 231 nM, respectively) and inhibition of K562 cell growth (IC50 = 0.5 and IC50 = 1.6 μM). 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 = 84 nM), did not inhibit cancer cell proliferation. (3) Mycophenolic-(l)-and (d)-valine adenine di-amide derivatives 25 (Ki = 9 nM) and 28 (Ki = 3 nM) were found to be very potent enzymatically, but did not inhibit proliferation of cancer cells.
KW - Inosine monophosphate dehydrogenase
KW - Mycophenolic acid
KW - Mycophenolic adenine dinucleotides
KW - Nicotinamide adenine dinucleotide
KW - Novel IMPDH inhibitors
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UR - http://www.scopus.com/inward/citedby.url?scp=84891440411&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2013.11.005
DO - 10.1016/j.bmcl.2013.11.005
M3 - Article
C2 - 24269162
AN - SCOPUS:84891440411
SN - 0960-894X
VL - 24
SP - 332
EP - 336
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 1
ER -