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

Bioorg Med Chem. 2013 Jun 1;21(11):3147-53. doi: 10.1016/j.bmc.2013.03.033. Epub 2013 Apr 6.

Abstract

A series of 4-anilinoquinoline derivatives related to the known inhibitor SGI-1027, containing side chains of varying pK(a), 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 pK(a) of the quinoline unit had little apparent influence on activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / chemical synthesis*
  • Aniline Compounds / chemistry
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases / antagonists & inhibitors*
  • DNA (Cytosine-5-)-Methyltransferases / chemistry
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • Gene Expression / drug effects
  • HCT116 Cells
  • Humans
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / genetics
  • Quinolines / chemical synthesis*
  • Quinolines / chemistry
  • Structure-Activity Relationship*

Substances

  • Aniline Compounds
  • Antineoplastic Agents
  • Neoplasm Proteins
  • Quinolines
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases
  • DNMT1 protein, human