42747-84-2

Upstream product

• 4318-56-3 3-methyl-6-chlorouracil 
• 60-34-4 methylhydrazine 

Downstream Products

• 76629-63-5 1-methyl-3-p-tolylamino-4,6-dioxotetrahydro-5-methylpyrazolo<3,4-d>-pyrimidine 
• 76629-62-4 1-methyl-1-(3-methyl-2,4-dioxotetrahydropyrimido-6-yl)-4-phenylthiosemicarbazide 
• 68871-26-1 4,8-dihydro-3-phenyl-4-deazatoxoflavin 
• 68871-22-7 1,7-dimethyl-6,8-dioxo-3-phenyl-1,4,6,7,8-pentahydropyrimido<4,3-c>-as-triazine 
• 68871-17-0 1,6-dimethyl-3-phenylpyrimido[4,5-c]pyridazine-5,7(1H,6H)-dione 
• 78431-32-0 3,7-dimethyl-2,4,6,8-tetraoxo-1,2,3,4,6,7,8,9-octahydropyrido<2,3-d:6,5-d'>dipyrimidine 
• 58695-94-6 3,4-diphenyl-1,6-dimethyl-4-deazatoxoflavin 
• 1025674-54-7 C₁₇H₂₂N₄O₂ 
• 905787-75-9 C₁₄H₁₆N₄O₂ 
• 78431-33-1 6-(2-(4-fluorobenzylidene)-1-methylhydrazinyl)-3-methylpyrimidine-2,4(1H,3H)-dione 
• 32502-54-8 6-(2-(4-chlorobenzylidene)-1-methylhydrazinyl)-3-methylpyrimidine-2,4(1H,3H)-dione 
• 1025163-76-1 C₁₃H₁₃ClN₄O₂ 
• 42748-18-5 6-(2-(4-methoxybenzylidene)-1-methylhydrazinyl)-3-methylpyrimidine-2,4(1H,3H)-dione 
• 78431-34-2 C₁₃H₁₂Cl₂N₄O₂ 

Relevant academic research and scientific papers

Rational design, synthesis and biological profiling of new KDM4C inhibitors

The human histone demethylases of the KDM4 family have been related to diseases such as prostate and breast cancer. Majority of currently known inhibitors suffer from the low permeability and low selectivity between the enzyme isoforms. In this study, toxoflavin motif was used to design and synthesize new KDM4C inhibitors with improved biological activity and in vitro ADME properties. Inhibitors displayed good passive cellular permeability and metabolic stability. However, diminishing of redox liability and consequently non-specific influence on cell viability still remains a challenge.

Discovery and Mechanistic Elucidation of a Class of Protein Disulfide Isomerase Inhibitors for the Treatment of Glioblastoma

Protein disulfide isomerase (PDI) is overexpressed in glioblastoma, the most aggressive form of brain cancer, and folds nascent proteins responsible for the progression and spread of the disease. Herein we describe a novel nanomolar PDI inhibitor, pyrimidotriazinedione 35G8, that is toxic in a panel of human glioblastoma cell lines. We performed a medium-throughput 20 000-compound screen of a diverse subset of 1 000 000 compounds to identify cytotoxic small molecules. Cytotoxic compounds were screened for PDI inhibition, and, from the screen, 35G8 emerged as the most cytotoxic inhibitor of PDI. Bromouridine labeling and sequencing (Bru-seq) of nascent RNA revealed that 35G8 induces nuclear factor-like 2 (Nrf2) antioxidant response, endoplasmic reticulum (ER) stress response, and autophagy. Specifically, 35G8 upregulated heme oxygenase 1 and solute carrier family 7 member 11 (SLC7A11) transcription and protein expression and repressed PDI target genes such as thioredoxin-interacting protein 1 (TXNIP) and early growth response 1 (EGR1). Interestingly, 35G8-induced cell death did not proceed via apoptosis or necrosis, but by a mixture of autophagy and ferroptosis. Cumulatively, our data demonstrate a mechanism for a novel PDI inhibitor as a chemical probe to validate PDI as a target for brain cancer.

Convenient synthesis of toxoflavin that targets β-catenin/TCF4 signaling activities

A rapid and improved route for synthesis of toxoflavin, an antibiotic and antitumor agent, is described. The method uses easily obtained materials and simple and practical reactions, including chlorination, condensation, and diazotization to produce toxoflavin in five steps with 14.2% yield and 98.6% purity (HPLC). This synthetic toxoflavin effectively inhibited β-catenin/Tcf4 driven TOP-luciferase activity with an IC50 of less than 0.5 μM and induced colon cancer cell death in a dose-dependent manner with an IC50 of 0.29 μM.

Investigation of 3-aryl-pyrimido[5,4-e][1,2,4]triazine-5,7-diones as small molecule antagonists of β-catenin/TCF transcription

Nearly all colorectal cancers (CRCs) and varied subsets of other cancers have somatic mutations leading to β-catenin stabilization and increased β-catenin/TCF transcriptional activity. Inhibition of stabilized β-catenin in CRC cell lines arrests their growth and highlights the potential of this mechanism for novel cancer therapeutics. We have pursued efforts to develop small molecules that inhibit β-catenin/TCF transcriptional activity. We used xanthothricin, a known β-catenin/TCF antagonist of microbial origin, as a lead compound to synthesize related analogues with drug-like features such as low molecular weight and good metabolic stability. We studied a panel of six candidate Wnt/β-catenin/Tcf- regulated genes and found that two of them (Axin2, Lgr5) were reproducibly activated (9-10 fold) in rat intestinal epithelial cells (IEC-6) following β-catenin stabilization by Wnt-3a ligand treatment. Two previously reported β-catenin/TCF antagonists (calphostin C, xanthothricin) and XAV939 (tankyrase antagonist) inhibited Wnt-activated genes in a dose-dependent fashion. We found that four of our compounds also potently inhibited Wnt-mediated activation in the panel of target genes. We investigated the mechanism of action for one of these (8c) and demonstrated these novel small molecules inhibit β-catenin transcriptional activity by degrading β-catenin via a proteasome-dependent, but GSK3β-, APC-, AXIN2- and βTrCP-independent, pathway. The data indicate the compounds act at the level of β-catenin to inhibit Wnt/β-catenin/TCF function and highlight a robust strategy for assessing the activity of β-catenin/TCF antagonists.

Toxoflavins and deazaflavins as the first reported selective small molecule inhibitors of tyrosyl-DNA phosphodiesterase II

The recently discovered enzyme tyrosyl-DNA phosphodiesterase 2 (TDP2) has been implicated in the topoisomerase-mediated repair of DNA damage. In the clinical setting, it has been hypothesized that TDP2 may mediate drug resistance to topoisomerase II (topo II) inhibition by etoposide. Therefore, selective pharmacological inhibition of TDP2 is proposed as a novel approach to overcome intrinsic or acquired resistance to topo II-targeted drug therapy. Following a high-throughput screening (HTS) campaign, toxoflavins and deazaflavins were identified as the first reported sub-micromolar and selective inhibitors of this enzyme. Toxoflavin derivatives appeared to exhibit a clear structure-activity relationship (SAR) for TDP2 enzymatic inhibition. However, we observed a key redox liability of this series, and this, alongside early in vitro drug metabolism and pharmacokinetics (DMPK) issues, precluded further exploration. The deazaflavins were developed from a singleton HTS hit. This series showed distinct SAR and did not display redox activity; however low cell permeability proved to be a challenge.

Microwave-assisted synthesis of 3-aryl-pyrimido[5,4-e][1,2,4]triazine-5, 7(1H,6H)-dione libraries: Derivatives of toxoflavin

The parallel synthesis of a library of toxoflavin derivatives is described. The microwave-assisted approach involves the de novo generation of the heterocyclic scaffold and allows for facile introduction of a variety of fragments.

Synthesis, properties, and redox ability of optically active 3-carbamoyl-1,6-dimethylpyrimido[4,5-c]pyridazine-5,7(1H,6H)-dione and related pyrimido-annulated pyridine analogues

Optically active 3-carbamoyl-1,6-dimethylpyrimido[4,5-c]pyridazine-5,7(1H,6H)-dione (13a) and related pyrimido-annulated pyridine analogues (13b,c) were prepared via the corresponding 3-ethoxycarbonyl-1,6-dimethylpyrimido[4,5-c]pydazine-5,7(1H,6H)-dione (11a) and the related compounds (11b,c). The properties of 11a-c, 13a-c, and the related 1,3,6-trimethylpyrimido[4,5-c]pyridazine-5,7(1H,6H)-dione (18a) as well as 7-phenyl-and 3,7,8-trimethyl-pyrido[2,3-d]pyrimidine-2,4(3H,8H)-dione (18b,c) having no carbamoyl or ester function were studied by the UV-VIS spectra and redox potentials. Although pyridazine derivative (13a) was not reduced, pyridine derivatives (11b,c), (13b), and (18b) were reduced by Na 2S2O4 to give dihydrogenated compounds (20b,c), (21b), and (22b), respectively. The photo-induced oxidation reactions of 13a,b and 18a-c toward some amines under aerobic conditions were studied to give the corresponding imines in more than 100% yields [based on compounds 13a,b and 18a-c], suggesting that the oxidation proceeds in an autorecycling process.

3-PHENYL ANALOGS OF TOXOFLAVINE AS KINASE INHIBITORS

The present invention concerns the compounds of formula (I) the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein n represents an integer being 0, 1 or 2; m represents an integer being 0 or 1; R1 represents C I -4alkyl; R2 represents C I -4alkyl; R3 represents CI-4alkyl; or R2 and R3 taken together with the carbon atom to which they are attached form a C3-8cycloalkyl or Het1 wherein said C3-8cycloalkyl or Het1 each independently may optionally be substituted with C1-4alkyloxycarbonyl; R4 represents halo or C I -4alkyloxy; R5 represents C 1-4alkyloxycarbonyl, -O-(mono- or di(C1-4alkyl)aminosulfonyl), CI-4alkyl substituted with one or where possible more substituent being selected from Het3 or NR6R7, C1-4alkyloxy substituted with one or where possible more substituents being selected from amino, Het4or NR8R9; R6 and R7are each independently selected from hydrogen, C I-4alkyl, C I-4alkyloxyC1-4alkyl, -Het5 or CI-4alkyl substituted with one or where possible more substituents being selected from hydroxy, or Het5; R8 and R9 are each independently selected from hydrogen, C,1-4alkyl, -Het7 or mono- or di(C 1-4alkyl)aminosulphonyl; Het3represents a heterocycle selected from piperidinyl, or piperazinyl wherein said monocyclic heterocycles each independently may optionally be substituted with one, or where possible two or three substituents each independently selected from hydroxy, aminosulfonyl, amino, mono-or di(C 1-4 alkyl)aminosulfonyl, hydroxyC 1-4alkyloxyC1-4alkyl or C1-4alkyloxy; Het4represents a heterocycle selected from morpholinyl, piperidinyl or piperazinyl wherein said monocyclic heterocycles each independently may optionally be substituted with one, or where possible two or three substituents each independently selected from C1-4alkyl, C1-4alkyloxycarbonyl or mono- or di(C1-4alkyl)aminosulfonyl; Het5 represents a heterocycle selected from pyridinyl or piperidinyl wherein said monocyclic heterocycles each independently may optionally be substituted with one, or where possible two or three substituents each independently selected from aminosulfonyl, or mono- or di(Cl-4alkyl)aminosulfonyl; Het7 represents piperidinyl.