Structure–activity relationships for 4-anilinoquinoline derivatives as inhibitors of the DNA methyltransferase enzyme DNMT1

• Published in: Bioorganic & medicinal chemistry 2013-06, Vol.21 (11), p.3147-3153
• Main Authors: Gamage, Swarna A., Brooke, Darby G., Redkar, Sanjeev, Datta, Jharna, Jacob, Samson T., Denny, William A.
• Format: Article
• Language: English
• Subjects: Aniline Compounds - chemical synthesis; Aniline Compounds - chemistry; Anilinoquinoline; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; colorectal neoplasms; DNA; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases - antagonists & inhibitors; DNA (Cytosine-5-)-Methyltransferases - chemistry; DNA (Cytosine-5-)-Methyltransferases - genetics; DNMT1 inhibitor; Gene Expression - drug effects; HCT116 Cells; Humans; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - chemistry; Neoplasm Proteins - genetics; Quinoline; Quinolines - chemical synthesis; Quinolines - chemistry; Structure-Activity Relationship; structure-activity relationships; Synthesis; Western blotting
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2013.03.033

A series of 4-anilinoquinoline derivatives related to the known inhibitor SGI-1027, containing side chains of varying pKa, were prepared by acid-catalysed coupling of the pre-formed side chains with 4-chloroquinolines. The compounds were evaluated for their ability to reduce the level of DNMT1 protein in HCT116 human colon carcinoma cells by Western blotting. With a very strongly basic N-methylpyridinium side chain, only NHCO-linked compounds were effective, whereas less strongly basic ((diaminomethylene)hydrazono)ethyl or 3-methylpyrimidine-2,4-diamine side chains allowed both NHCO- and CONH-linked compounds to show activity. In contrast, the pKa of the quinoline unit had little apparent influence on activity.