2′,6′-Dihalostyrylanilines, pyridines, and pyrimidines for the inhibition of the catalytic subunit of methionine s-adenosyltransferase-2

Vitaliy M. Sviripa, Wen Zhang, Andrii G. Balia, Oleg V. Tsodikov, Justin R. Nickell, Florence Gizard, Tianxin Yu, Eun Y. Lee, Linda P. Dwoskin, Chunming Liu, David S. Watt

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Inhibition of the catalytic subunit of the heterodimeric methionine S-adenosyl transferase-2 (MAT2A) with fluorinated N,N-dialkylaminostilbenes (FIDAS agents) offers a potential avenue for the treatment of liver and colorectal cancers where upregulation of this enzyme occurs. A study of structure-activity relationships led to the identification of the most active compounds as those with (1) either a 2,6-difluorostyryl or 2-chloro-6- fluorostyryl subunit, (2) either an N-methylamino or N,N-dimethylamino group attached in a para orientation relative to the 2,6-dihalostyryl subunit, and (3) either an N-methylaniline or a 2-(N,N-dimethylamino)pyridine ring. These modifications led to FIDAS agents that were active in the low nanomolar range, that formed water-soluble hydrochloride salts, and that possessed the desired property of not inhibiting the human hERG potassium ion channel at concentrations at which the FIDAS agents inhibit MAT2A. The active FIDAS agents may inhibit cancer cells through alterations of methylation reactions essential for cancer cell survival and growth.

Original languageEnglish
Pages (from-to)6083-6091
Number of pages9
JournalJournal of Medicinal Chemistry
Volume57
Issue number14
DOIs
StatePublished - Jul 24 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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