Structure-Activity Relationships of Orotidine-5′-Monophosphate Decarboxylase Inhibitors as Anticancer Agents
Structure-Activity Relationships of Orotidine-5′-Monophosphate Decarboxylase Inhibitors as Anticancer Agents
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DOI：
10.1021/jm801224t
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发表时间：
2009-03-26
影响因子：
7.3
通讯作者：
Kotra, Lakshmi P.
中科院分区：
文献类型：
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作者：
Bello, Angelica M.;Konforte, Danijela;Kotra, Lakshmi P.
合成了一系列6-取代和5-氟-6-取代尿苷衍生物，并对其作为抗癌药物的潜力进行了评价。所设计的分子由完全保护的尿苷或相应的5-氟尿苷衍生物合成。将monoclastide衍生物用于针对ODCase的酶抑制研究。所有合成的衍生物的抗癌活性进行了评价，使用核苷形式的抑制剂。5-Fluoro-UMP是一种非常弱的ODCase抑制剂。6-叠氮基-5-氟和5-氟-6-碘衍生物是ODCase的共价抑制剂，并且活性位点Lys 145残基在6-取代消除后共价结合配体。在合成的核苷衍生物中，6-叠氮基-5-氟、6-氨基-5-氟和6-甲醛-5-氟衍生物在针对各种白血病细胞系的基于细胞的测定中显示出有效的抗癌活性。在此基础上，6-叠氮基-5-氟和6-氨基-5-氟尿苷衍生物具有进一步研究的潜力。
A series of 6-substituted and 5-fluoro-6-substituted uridine derivatives were synthesized and evaluated for their potential as anticancer agents. The designed molecules were synthesized from either fully protected uridine or the corresponding 5-fluorouridine derivatives. The mononucleotide derivatives were used for enzyme inhibition investigations against ODCase. Anticancer activities of all the synthesized derivatives were evaluated using the nucleoside forms of the inhibitors. 5-Fluoro-UMP was a very weak inhibitor of ODCase. 6-Azido-5-fluoro and 5-fluoro-6-iodo derivatives are covalent inhibitors of ODCase, and the active site Lys145 residue covalently binds to the ligand after the elimination of the 6-substitution. Among the synthesized nucleoside derivatives, 6-azido-5-fluoro, 6-amino-5-fluoro, and 6-carbaldehyde-5-fluoro derivatives showed potent anticancer activities in cell-based assays against various leukemia cell lines. On the basis of the overall profile, 6-azido-5-fluoro and 6-amino-5-fluoro uridine derivatives exhibited potential for further investigations.