10.1016/j.ejmech.2013.02.007
The research aims to develop specific inhibitors targeting isoprenylcysteine carboxyl methyltransferase (Icmt), an enzyme implicated in post-translational modification of proteins associated with cell growth regulation and oncogenesis. The inhibition of Icmt is considered a potential therapeutic strategy for cancer treatment. The researchers systematically modified the known Icmt inhibitor cysmethynil to enhance its solubility and permeability while improving its inhibitory activity. The modifications included replacing the amide side chain with a tertiary amine and introducing an aminopyrimidine ring instead of an m-tolyl group. The study identified compound 15, featuring a 2-aminopyrimidin-5-yl group, as a promising drug-like substitute with improved solubility, PAMPA permeability, and antiproliferative activity against various malignant cell lines. The research concluded that the presence of the polar aminopyrimidine ring significantly contributed to the potency and drug-like profile of the final compound, although concerns about the toxic potential of the indoleamine chemotype remain. Key chemicals used in the process include cysmethynil, various substituted phenyl, pyridine, and pyrimidine boronic acids, as well as reagents for the synthesis and evaluation of the target compounds, such as S-adenosylmethionine (SAM), biotin-S-farnesyl-L-cysteine (BFC), and tritiated SAM for Icmt inhibitory activity assessment, and a range of human cancer cell lines for antiproliferative activity evaluation.
10.1002/anie.202004963
The study explores the potential of re-engineering methyltransferase enzymes (MTs) to utilize carboxy-S-adenosyl-L-methionine (cxSAM) as an alternative cofactor to the commonly used S-adenosyl-L-methionine (SAM), enabling the generation of carboxymethylated products instead of the usual methylated ones. The researchers used site-directed mutagenesis to create orthogonal MTs, specifically focusing on catechol-O-methyltransferase (COMT) and coclaurine-N-methyltransferase (CNMT), with improved catalytic activity and selectivity for cxSAM. They demonstrated that these engineered enzymes, when coupled with the cxSAM synthase (CmoA), could efficiently and selectively carboxymethylate tetrahydroisoquinoline (THIQ) and catechol substrates. Additionally, the study introduced a novel co-factor, carboxy-S-adenosyl-L-ethionine (cxSAE), which facilitated the stereoselective transfer of a chiral 1-carboxyethyl group to the substrate. This work provides a platform for engineering common methylation pathways to deliver carboxymethylated products with new properties and functionalities, potentially expanding the scope of bioalkylation pathways both in vitro and in vivo.
10.1021/jm00223a022
The research explore the relationship between the structure of substituted 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines (THIQs) and their biological activities, specifically their interactions with catechol O-methyltransferase (COMT) and their ability to release norepinephrine from mouse hearts. The study synthesized various 2- and 4-substituted THIQs and evaluated their substrate and inhibitory kinetic properties towards COMT. It was found that methyl substituents in the 2 and/or 4 positions had little effect on the interaction of these molecules with COMT, as the substrate kinetic (Km, Vmax) and inhibitory kinetic (Ki) properties were similar across the compounds. However, the norepinephrine depleting activity showed stricter structural requirements, with methyl substituents generally eliminating this activity, except for 6,7-dihydroxy-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolinium iodide, which was more active than the parent molecule. The key chemicals used included 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, various substituted derivatives thereof, S-adenosyl-L-methionine (SAM) as a methyl donor, and DL-norepinephrine-7-3H for the norepinephrine release assays. The study concluded that minor structural modifications of 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline could separate the COMT inhibitory effects from the indirect sympathomimetic effects, suggesting potential for developing new COMT inhibitors with reduced sympathomimetic activity.
