Rapid Synthesis of New DNMT Inhibitors Derivatives of Procainamide

被引：51

作者：

Halby, Ludovic ^{[1
,2
,3
]}

Champion, Christine ^{[2
,3
]}

Senamaud-Beaufort, Catherine ^{[2
]}

Ajjan, Sophie ^{[2
,3
]}

Drujon, Thierry ^{[4
,5
]}

Rajavelu, Arumugam ^{[6
]}

Ceccaldi, Alexandre ^{[2
,3
]}

Jurkowska, Renata ^{[6
]}

Lequin, Olivier ^{[4
,5
]}

Nelson, William G. ^{[7
]}

Guy, Alain ^{[1
]}

Jeltsch, Albert ^{[6
]}

Guianvarc'h, Dominique ^{[4
,5
]}

Ferroud, Clotilde ^{[1
]}

Arimondo, Paola B. ^{[2
]}

机构：

[1] CNAM UMR 7084 CNRS, F-75003 Paris, France

[2] CNRS MNHN UMR 7196 INSERM U565, F-75005 Paris, France

[3] Univ Paris 06, F-75005 Paris, France

[4] UMR 7203 CNRS UPMC ENS, F-75005 Paris, France

[5] FR2769, F-75005 Paris, France

[6] Jacobs Univ Bremen, Sch Sci & Engn, D-28759 Bremen, Germany

[7] Johns Hopkins Univ, Baltimore, MD 21231 USA

来源：

CHEMBIOCHEM | 2012年 / 13卷 / 01期

关键词：

cancer; conjugation; DNA methylation; inhibitors; rapid synthesis; MAMMALIAN DNA METHYLTRANSFERASES; FORMING OLIGONUCLEOTIDES; PROMISCUOUS INHIBITORS; CELL-LINES; METHYLATION; CANCER; EPIGENETICS; TOPOISOMERASE; CLEAVAGE; HYDRALAZINE;

D O I：

10.1002/cbic.201100522

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

DNA methyltransferases (DNMTs) are responsible for DNA methylation, an epigenetic modification involved in gene regulation. Families of conjugates of procainamide, an inhibitor of DNMT1, were conceived and produced by rapid synthetic pathways. Six compounds resulted in potent inhibitors of the murine catalytic Dnmt3A/3L complex and of human DNMT1, at least 50 times greater than that of the parent compounds. The inhibitors showed selectivity for C5 DNA methyltransferases. The cytotoxicity of the inhibitors was validated on two tumour cell lines (DU145 and HCT116) and correlated with the DNMT inhibitory potency. The inhibition potency of procainamide conjugated to phthalimide through alkyl linkers depended on the length of the linker; the dodecane linker was the best.

引用

页码：157 / 165

页数：9

共 37 条

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