M.W=300-350 | Pyrimidines

Hanaoka, Kenjiro’s team published research in Scientific Reports in 7 | CAS: 459420-09-8

Scientific Reports published new progress about 459420-09-8. 459420-09-8 belongs to pyrimidines, auxiliary class Metabolic Enzyme,3MST, name is 6-Methyl-2-((2-(naphthalen-1-yl)-2-oxoethyl)thio)pyrimidin-4(3H)-one, and the molecular formula is C17H14N2O2S, Safety of 6-Methyl-2-((2-(naphthalen-1-yl)-2-oxoethyl)thio)pyrimidin-4(3H)-one.

Hanaoka, Kenjiro published the artcileDiscovery and Mechanistic Characterization of Selective Inhibitors of H₂S-producing Enzyme: 3-Mercaptopyruvate Sulfurtransferase (3MST) Targeting Active-site Cysteine Persulfide, Safety of 6-Methyl-2-((2-(naphthalen-1-yl)-2-oxoethyl)thio)pyrimidin-4(3H)-one, the publication is Scientific Reports (2017), 40227, database is CAplus and MEDLINE.

Very recent studies indicate that sulfur atoms with oxidation state 0 or -1, called sulfane sulfurs, are the actual mediators of some physiol. processes previously considered to be regulated by hydrogen sulfide (H₂S). 3-Mercaptopyruvate sulfurtransferase (3MST), one of three H₂S-producing enzymes, was also recently shown to produce sulfane sulfur (H₂S_n). Here, we report the discovery of several potent 3MST inhibitors by means of high-throughput screening (HTS) of a large chem. library (174,118 compounds) with our H₂S-selective fluorescent probe, HSip-1. Most of the identified inhibitors had similar aromatic ring-carbonyl-S-pyrimidone structures. Among them, compound 3 showed very high selectivity for 3MST over other H₂S/sulfane sulfur-producing enzymes and rhodanese. The X-ray crystal structures of 3MST complexes with two of the inhibitors revealed that their target is a persulfurated cysteine residue located in the active site of 3MST. Precise theor. calculations indicated the presence of a strong long-range electrostatic interaction between the persulfur anion of the persulfurated cysteine residue and the pos. charged carbonyl carbon of the pyrimidone moiety of the inhibitor. Our results also provide the exptl. support for the idea that the 3MST-catalyzed reaction with 3-mercaptopyruvate proceeds via a ping-pong mechanism.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/Pyrimidine,
Pyrimidine – Wikipedia

Augsburger, Fiona’s team published research in Biomolecules in 10 | CAS: 459420-09-8

Biomolecules published new progress about 459420-09-8. 459420-09-8 belongs to pyrimidines, auxiliary class Metabolic Enzyme,3MST, name is 6-Methyl-2-((2-(naphthalen-1-yl)-2-oxoethyl)thio)pyrimidin-4(3H)-one, and the molecular formula is C17H14N2O2S, Category: pyrimidines.

Augsburger, Fiona published the artcileRole of 3-mercaptopyruvate sulfurtransferase in the regulation of proliferation, migration, and bioenergetics in murine colon cancer cells, Category: pyrimidines, the publication is Biomolecules (2020), 10(3), 447, database is CAplus and MEDLINE.

The current study was designed to investigate the functional role of 3-MST’s catalytic activity in the murine colon cancer cell line CT26. The novel pharmacol. 3-MST inhibitor HMPSNE was used to assess cancer cell proliferation, migration and bioenergetics in vitro. Methods included measurements of cell viability (MTT and LDH assays), cell proliferation and in vitro wound healing (IncuCyte) and cellular bioenergetics (Seahorse extracellular flux anal.). 3-MST expression was detected by Western blotting; H₂S production was measured by the fluorescent dye AzMC. The results show that CT26 cells express 3-MST protein and mRNA, as well as several enzymes involved in H₂S degradation (TST, ETHE1). HMPSNE exerted a bell-shaped effect on several cellular bioenergetic parameters related to oxidative phosphorylation, while other bioenergeticparameterswereeitherunaffectedorinhibitedatthehighestconcentrationoftheinhibitor tested (300μM). In contrast to 3-MST, the expression of CBS (another H₂S producing enzyme which has been previously implicated in the regulation of various biol. parameters in other tumor cells) was not detectable in CT26 cells and pharmacol. inhibition of CBS exerted no significant effects on CT26 proliferation or bioenergetics. In summary, 3-MST catalytic activity significantly contributes to the regulation of cellular proliferation, migration and bioenergetics in CT26 murine colon cancer cells.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/Pyrimidine,
Pyrimidine – Wikipedia

Ascencao, Kelly’s team published research in Pharmacological Research in 165 | CAS: 459420-09-8

Pharmacological Research published new progress about 459420-09-8. 459420-09-8 belongs to pyrimidines, auxiliary class Metabolic Enzyme,3MST, name is 6-Methyl-2-((2-(naphthalen-1-yl)-2-oxoethyl)thio)pyrimidin-4(3H)-one, and the molecular formula is C17H14N2O2S, Name: 6-Methyl-2-((2-(naphthalen-1-yl)-2-oxoethyl)thio)pyrimidin-4(3H)-one.

Ascencao, Kelly published the artcilePharmacological induction of mesenchymal-epithelial transition via inhibition of H₂S biosynthesis and consequent suppression of ACLY activity in colon cancer cells, Name: 6-Methyl-2-((2-(naphthalen-1-yl)-2-oxoethyl)thio)pyrimidin-4(3H)-one, the publication is Pharmacological Research (2021), 105393, database is CAplus and MEDLINE.

Hydrogen sulfide (H₂S) is an important endogenous gaseous transmitter mediator, which regulates a variety of cellular functions in autocrine and paracrine manner. The enzymes responsible for the biol. generation of H₂S include cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST). Increased expression of these enzymes and overproduction of H₂S has been implicated in essential processes of various cancer cells, including the stimulation of metabolism, maintenance of cell proliferation and cytoprotection. Cancer cell identity is characterized by so-called “transition states”. The progression from normal (epithelial) to transformed (mesenchymal) state is termed epithelial-to-mesenchymal transition (EMT) whereby epithelial cells lose their cell-to-cell adhesion capacity and gain mesenchymal characteristics. The transition process can also proceed in the opposite direction, and this process is termed mesenchymal-to-epithelial transition (MET). The current project was designed to determine whether inhibition of endogenous H₂S production in colon cancer cells affects the EMT/MET balance in vitro. Inhibition of H₂S biosynthesis in HCT116 human colon cancer cells was achieved either with aminooxyacetic acid (AOAA) or 2-[(4-hydroxy-6-methylpyrimidin-2-yl)sulfanyl]-1-(naphthalen-1-yl)ethan-1-one (HMPSNE). These inhibitors induced an upregulation of E-cadherin and Zonula occludens-1 (ZO-1) expression and downregulation of fibronectin expression, demonstrating that H₂S biosynthesis inhibitors can produce a pharmacol. induction of MET in colon cancer cells. These actions were functionally reflected in an inhibition of cell migration, as demonstrated in an in vitro “scratch wound” assay. The mechanisms involved in the action of endogenously produced H₂S in cancer cells in promoting (or maintaining) EMT (or tonically inhibiting MET) relate, at least in part, in the induction of ATP citrate lyase (ACLY) protein expression, which occurs via upregulation of ACLY mRNA (via activation of the ACLY promoter). ACLY in turn, regulates the Wnt-β-catenin pathway, an essential regulator of the EMT/MET balance. Taken together, pharmacol. inhibition of endogenous H₂S biosynthesis in cancer cells induces MET. We hypothesize that this may contribute to anti-cancer / anti-metastatic effects of H₂S biosynthesis inhibitors.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/Pyrimidine,
Pyrimidine – Wikipedia

Bantzi, Marina’s team published research in Journal of Medicinal Chemistry in 64 | CAS: 459420-09-8

Journal of Medicinal Chemistry published new progress about 459420-09-8. 459420-09-8 belongs to pyrimidines, auxiliary class Metabolic Enzyme,3MST, name is 6-Methyl-2-((2-(naphthalen-1-yl)-2-oxoethyl)thio)pyrimidin-4(3H)-one, and the molecular formula is C17H14N2O2S, Computed Properties of 459420-09-8.

Bantzi, Marina published the artcileNovel Aryl-Substituted Pyrimidones as Inhibitors of 3-Mercaptopyruvate Sulfurtransferase with Antiproliferative Efficacy in Colon Cancer, Computed Properties of 459420-09-8, the publication is Journal of Medicinal Chemistry (2021), 64(9), 6221-6240, database is CAplus and MEDLINE.

The enzyme 3-mercaptopyruvate sulfurtransferase (3-MST) is one of the more recently identified mammalian sources of H₂S. A recent study identified several novel 3-MST inhibitors with micromolar potency. Among those, (2-[(4-hydroxy-6-methylpyrimidin-2-yl)sulfanyl]-1-(naphthalen-1-yl)ethan-1-one) or HMPSNE was found to be the most potent and selective. Authours now took the central core of this compound and modified the pyrimidone and the arylketone sides independently. A 63-compound library was synthesized; compounds were tested for H₂S generation from recombinant 3-MST in vitro. Active compounds were subsequently tested to elucidate their potency and selectivity. Computer modeling studies have delineated some of the key structural features necessary for binding to the 3-MST’s active site. Six novel 3-MST inhibitors were tested in cell-based assays: they exerted inhibitory effects in murine MC38 and CT26 colon cancer cell proliferation; the antiproliferative effect of the compound with the highest potency and best cell-based activity (2-((2-(Naphthalen-1-yl)-2-oxoethyl)thio)pyrimidin-4(3H)-one) was also confirmed on the growth of MC38 tumors in mice.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/Pyrimidine,
Pyrimidine – Wikipedia