2′,6′-Dihalostyrylanilines, Pyridines, and Pyrimidines for the Inhibition of the Catalytic Subunit of Methionine S-Adenosyltransferase-2

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.

Application of Mannich bases to the synthesis of hydroxymethylated isoflavonoids as potential antineoplastic agents

“…Our past experience along these same lines in developing inhibitors that affect Wnt signaling encouraged these efforts. 10,11 …”

Phenylethynyl-substituted heterocycles inhibit cyclin D1 and induce the expression of cyclin-dependent kinase inhibitor p21Wif1/Cip1in colorectal cancer cells

“…Because heterocyclic variants in the stilbene series 13 in which the N,N -dimethylaniline ring in 1 was replaced by either an N,N -dimethylaminopyridine or an N,N -dimethylaminopyrimidine ring exhibited improved solubility and minimal hERG activation, we next focused on replacing the N,N -dimethylaniline ring in the diarylacetylene series with a heterocyclic ring as in the phenylethynyl-substituted heterocycles 5 (Fig. 1).…”

“…We reported, for example, that the 2′,6′-dihalostyrylanilines 1 (Fig. 1) inhibited the expression of Wnt target genes, such as c-myc, 10 and repressed colon cancer LS174T cell growth in vitro and in vivo 11–13 . We established that this agent targeted exclusively the catalytic subunit of the oligomeric enzyme, methionine S-adenosyltranferase-2 (MAT2) that furnishes S-adenosylmethionine (SAM) to regulatory methyltransferases.…”

“…We established that this agent targeted exclusively the catalytic subunit of the oligomeric enzyme, methionine S-adenosyltranferase-2 (MAT2) that furnishes S-adenosylmethionine (SAM) to regulatory methyltransferases. We further established that heterocyclic variants 13 of these 2′,6′-dihalostyrylanilines 1 possessed minimal gross toxicity, no human ether-à-go-go - related protein (hERG) 14, 15 activation, reasonable bioavailability and pharmacokinetics. As desired, these stilbene-based agents did not affect methionine S-adenosyltransferase-1 (MAT1) 16–19 that served as the principal source of SAM necessary for other cellular needs.…”

Antineoplastic Isoflavonoids Derived from Intermediate ortho‐Quinone Methides Generated from Mannich Bases

“…For example, the elimination of hydroxyl groups in resveratrol, a hackneyed natural product with a multiplicity of biological effects, led to the fluorinated stilbenes. [8a, 9] These antineoplastic agents act as epigenetic regulators of a single molecular target, the catalytic subunit of methionine adenosyltransferase-2. Additional modifications of the stilbene pharmacophore led to the fluorinated 3-arylquinolines[8b] as antineoplastic agents that bind uniquely to the intermediate filament protein, vimentin, and promote the secretion of the natural tumor suppressor, Prostate apoptosis response-4 protein (Par-4).…”