S -Alkylated Homocysteine Derivatives:  New Inhibitors of Human Betaine-Homocysteine S-Methyltransferase

• Published in: Journal of medicinal chemistry Vol. 49; no. 13; pp. 3982 - 3989
• Main Authors: Jiracek, Jiri, Collinsova, Michaela, Rosenberg, Ivan, Budesinsky, Milos, Protivinska, Eva, Netusilova, Hana, Garrow, Timothy A
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 29.06.2006; Amer Chemical Soc
• Subjects: Analytical, structural and metabolic biochemistry; Betaine-Homocysteine S-Methyltransferase - antagonists & inhibitors; Betaine-Homocysteine S-Methyltransferase - chemistry; Biological and medical sciences; Butyrates - chemical synthesis; Butyrates - chemistry; Caproates - chemical synthesis; Caproates - chemistry; Chemistry, Medicinal; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Homocysteine - analogs & derivatives; Homocysteine - chemical synthesis; Homocysteine - chemistry; Humans; Life Sciences & Biomedicine; Medical sciences; Miscellaneous; Pentanoic Acids - chemical synthesis; Pentanoic Acids - chemistry; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Sulfides - chemical synthesis; Sulfides - chemistry; Transferases; RAT-LIVER; RISK-FACTOR; DISEASE; PURIFICATION; CAPILLARY-ZONE-ELECTROPHORESIS; METHIONINE METABOLISM; OLIGOMERIZATION; CHROMATOGRAPHY; ZINC-BINDING; PHOSPHINIC PSEUDOPEPTIDES; Human; Enzyme; Aliphatic compound; Transferases; Enzyme inhibitor; Betaine-homocysteine S-methyltransferase; Competitive inhibition; In vitro; Sulfur containing aminoacid; Methyltransferases; Structure activity relation; Carboxylic acid; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm050885v

A series of S-alkylated derivatives of homocysteine were synthesized and characterized as inhibitors of human recombinant betaine-homocysteine S-methyltransferase (BHMT). Some of these compounds inhibit BHMT with IC50 values in the nanomolar range. BHMT is very sensitive to the structure of substituents on the sulfur atom of homocysteine. The S-carboxybutyl and S-carboxypentyl derivatives make the most potent inhibitors, and an additional sulfur atom in the alkyl chain is well tolerated. The respective (R,S)-5-(3-amino-3-carboxy-propylsulfanyl)-pentanoic, (R,S)-6-(3-amino-3-carboxy-propylsulfanyl)-hexanoic, and (R,S)-2-amino-4-(2-carboxymethylsulfanyl-ethylsulfanyl)-butyric acids are very potent inhibitors and are the strongest ever reported. We determined that (R,S)-5-(3-amino-3-carboxy-propylsulfanyl)-pentanoic acid displays competitive inhibition with respect to betaine binding with a of 12 nM. Some of these compounds are currently being tested in mice to study the influence of BHMT on the metabolism of sulfur amino acids in vivo.