TY - JOUR
T1 - NAD-analogues as potential anticancer agents
T2 - Conformational restrictions as basis for selectivity
AU - Pankiewicz, Krzysztof W.
AU - Zatorski, Andrzej
AU - Watanabe, Kyoichi A.
PY - 1996
Y1 - 1996
N2 - Cofactor type inhibitors (NAD-analogues) of IMP-dehydrogenase (IMPDH) were synthesized and their application as potential anticancer agents are discussed. C-nucleoside isosteres of NAD, C-NAD and C-PAD, showed an effective competitive inhibition of IMPDH. C-NAD but not C-PAD caused extremely potent inhibition of alcohol dehydrogenase. We also synthesized compounds in which nicotinamide riboside was replaced with tiazofurin (TAD-analogues) and the 2′ and 3′-positions of adenosine part were fluorinated. The ribose ring of 2′-deoxy-2′-fluoroadenosine is in the C3′-endo conformation whereas 3′-deoxy-3′-fluoroadenosine favors the C2′-endo sugar pucker. These derivatives are good inhibitors of IMPDH type II, the isoenzyme dominant in neoplastic cells. In contrast, all these analogues showed rather week inhibitory activity against alcohol dehydrogenase. Nicotinamide riboside derivatives in which the base and the sugar are linked through an oxygen or a methylene bridge were synthesized. NAD-analogues containing such conformationally restricted nicotinamide nucleoside moiety (syn or anti) are expected to be selective inhibitors of B-specific (IMPDH) or A-specific dehydrogenases, respectively.
AB - Cofactor type inhibitors (NAD-analogues) of IMP-dehydrogenase (IMPDH) were synthesized and their application as potential anticancer agents are discussed. C-nucleoside isosteres of NAD, C-NAD and C-PAD, showed an effective competitive inhibition of IMPDH. C-NAD but not C-PAD caused extremely potent inhibition of alcohol dehydrogenase. We also synthesized compounds in which nicotinamide riboside was replaced with tiazofurin (TAD-analogues) and the 2′ and 3′-positions of adenosine part were fluorinated. The ribose ring of 2′-deoxy-2′-fluoroadenosine is in the C3′-endo conformation whereas 3′-deoxy-3′-fluoroadenosine favors the C2′-endo sugar pucker. These derivatives are good inhibitors of IMPDH type II, the isoenzyme dominant in neoplastic cells. In contrast, all these analogues showed rather week inhibitory activity against alcohol dehydrogenase. Nicotinamide riboside derivatives in which the base and the sugar are linked through an oxygen or a methylene bridge were synthesized. NAD-analogues containing such conformationally restricted nicotinamide nucleoside moiety (syn or anti) are expected to be selective inhibitors of B-specific (IMPDH) or A-specific dehydrogenases, respectively.
KW - Anticancer agents
KW - Inhibitors of IMP-dehydrogenase
KW - NAD-analogues
KW - Tiazofurin
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U2 - 10.18388/abp.1996_4552
DO - 10.18388/abp.1996_4552
M3 - Article
C2 - 8790723
AN - SCOPUS:0029687199
SN - 0001-527X
VL - 43
SP - 183
EP - 194
JO - Acta Biochimica Polonica
JF - Acta Biochimica Polonica
IS - 1
ER -