58915-47-2

Upstream product

• 36327-91-0 orotoaldehyde 
• 16953-46-1 6-oxo-2-thioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbaldehyde 
• 58668-24-9 (2,5-dioxo-imidazolidin-4-yliden)-acetic acid 
• 80140-18-7 methyl N¹,N³-dibenzyloxymethyl-orotate 
• 66-22-8 uracil 
• 15059-25-3 C₅H₆N₂O₄ 
• 5988-19-2 L-dihydroorotic acid 
• 119767-58-7 2,6-Dioxo-3,6-dihydro-2H-[1,3]oxazine-4-carboxylic acid 
• 16953-49-4 6-diethoxymethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one 
• 16953-48-3 6-diethoxymethyl-1H-pyrimidine-2,4-dione 
• 4628-39-1 6-carboxymethyluracil 
• 6953-78-2 2-thioorotic acid 
• 626-48-2 6-Methyluracil 
• 71625-12-2 2,3-Dibromo-4-oxo-4-ureido-butyric acid 

Downstream Products

• 5971-84-6 1,3-dibenzyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carboxylic acid 
• 216435-76-6 Cu(I) bis(triphenylphosphine) orotate 
• 173863-26-8 [Pt(P(CH₃)2C₆H₅)2(C₅H₂N₂O₄)] 
• 173863-25-7 [Pt(P(C₆H₅)3)2(C₅H₂N₂O₄)] 
• 173863-29-1 [Pd(C₂₆H₂₄P₂)(C₅H₂N₂O₄)] 
• 1147735-17-8 N-(4-(4-methoxyphenyl)-3-(4-nitrophenyl)thiazol-2(3H)-ylidene)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide 
• 1147735-18-9 N-(3-(2-nitrophenyl)-4-phenylthiazol-2(3H)-ylidene)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide 
• 1147735-14-5 N-[3-(4-methoxyphenyl)-4-phenylthiazol-2(3H)ylidene]-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide 
• 1147735-16-7 N-(3-(4-chlorophenyl)-4-phenylthiazol-2(3H)-ylidene)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide 
• 1147735-15-6 N-(3-(4-acetylphenyl)-4-phenylthiazol-2(3H)-ylidene)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide 
• 27067-77-2 magnesium orotate 
• 98136-42-6 2,6-dichloropyrimidine-4-carboxamide 
• 173863-32-6 [Pt(C₂₆H₂₄P₂)(C₅H₂N₂O₄)]*NC₅H₃(NH₂)2*CH₂Cl₂ 
• 1079649-91-4 2,4-dihydroxy-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one 

Relevant academic research and scientific papers

Multiple states of the Tyr318Leu mutant of dihydroorotate dehydrogenase revealed by single-molecule kinetics

Dihydroorotate dehydrogenase (DHOD) from Escherichia coli is a monomeric membrane-associated flavoprotein that catalyzes the oxidation of dihydroorotate to orotate. By using confocal fluorescence spectroscopy on the highly fluorescent Tyr318Leu DHOD mutant, we studied the catalytic turnover of single enzyme molecules through the characteristic on-off fluorescence signal, which corresponds to flavin mononucleotide (FMN) interconverting between the oxidized and reduced states during turnover. Our single-molecule data provide evidence of a distinct static heterogeneity in the enzymatic activity, with some molecules going through the on-off cycles 5-fold faster than others, however, there is no detectable dynamic disorder in DHOD turnover. When 0.1% reduced Triton X-100, a detergent that more closely simulates the natural membrane environment, is added, our data suggest the degree of static molecular heterogeneity is reduced. The observation of static heterogeneity suggests that the enzyme, which associates with the membrane in vivo, is present in distinct conformations that result in different catalytic efficiencies. The alternate conformations are most likely the result of the loss of van der Waals or other interactions between tyrosine 318 and FMN in the catalytic site with the mutation of Tyr318Leu, which disrupts the native structure of wild-type DHOD.

Brequinar derivatives and species-specific drug design for dihydroorotate dehydrogenase

Therapeutic agents brequinar sodium and leflunomide (Arava) work by binding in a hydrophobic tunnel formed by a highly variable N-terminus of family 2 dihydroorotate dehydrogenase (DHODH). The X-ray crystallographic structure of an analog of brequinar bound to human DHODH was determined. In silico screening of a library of compounds suggested another subset of brequinar analogs that do not inhibit human DHODH as potentially effective inhibitors of Plasmodium falciparum DHODH.

Targeting of hematologic malignancies with PTC299, a novel potent inhibitor of dihydroorotate dehydrogenase with favorable pharmaceutical properties

PTC299 was identified as an inhibitor of VEGFA mRNA translation in a phenotypic screen and evaluated in the clinic for treatment of solid tumors. To guide precision cancer treatment, we performed extensive biological characterization of the activity of PTC299 and demonstrated that inhibition of VEGF production and cell proliferation by PTC299 is linked to a decrease in uridine nucleotides by targeting dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme for de novo pyrimidine nucleotide synthesis. Unlike previously reported DHODH inhibitors that were identified using in vitro enzyme assays, PTC299 is a more potent inhibitor of DHODH in isolated mitochondria suggesting that mitochondrial membrane lipid engagement in the DHODH conformation in situ is required for its optimal activity. PTC299 has broad and potent activity against hematologic cancer cells in preclinical models, reflecting a reduced pyrimidine nucleotide salvage pathway in leukemia cells. Archived serum samples from patients treated with PTC299 demonstrated increased levels of dihydroorotate, the substrate of DHODH, indicating target engagement in patients. PTC299 has advantages over previously reported DHODH inhibitors, including greater potency, good oral bioavailability, and lack of off-target kinase inhibition and myelosuppression, and thus may be useful for the targeted treatment of hematologic malignancies.

Natural product piperine alleviates experimental allergic encephalomyelitis in mice by targeting dihydroorotate dehydrogenase

Multiple sclerosis (MS) is the most popular chronic and debilitating inflammatory disease of the central nervous system (CNS) that remains incurable. Dihydroorotate dehydrogenase (DHODH) is critical to the activity of T lymphocytes and represents a potential therapeutic target for MS. Here we identify piperine, a bioactive constituent of black pepper, as a potent inhibitor of DHODH with an IC50 value of 0.88 μM. Isothermal titration calorimetry and thermofluor assay demonstrate the directly interaction between piperine and DHODH. The co-complex crystal structure of DHODH and piperine at 1.98 ? resolution further reveal that Tyr356 residue of DHODH is crucial for piperine binding. Importantly, we show that piperine can inhibit T cell overactivation in a DHODH-dependent manner in concanavalin A-triggered T-cell assay and mixed lymphocyte reaction assay. Finally, piperine exhibits strong preventive and therapeutic effect in the MOG-induced experimental allergic encephalomyelitis (EAE), a useful model for studying potential treatments for MS, by restricting inflammatory cells infiltration into the CNS and preventing myelin destruction and blood–brain barrier (BBB) disruption. Taken together, these findings highlight DHODH as a therapeutic target for autoimmune disease of the nervous system, and demonstrate a novel role for piperine in the treatment of MS.

Stereoselectivity in the Enzymatic Oxidation and Nonenzymatic Hydrogen-Exchange Reactions of Dihydroorotate

(S)-5,6-Dihydroorotate (1) undergoes a stereoselective hydrogen-exchange reaction with solvent deuterons in deuterium oxide buffer (100 mM NaPi pD 7.8, 37 deg C).High-field (1)H NMR analysis of the exchange reveals the formation of (5R,6S)-dihydroorotate (3) in an apparent first-order process (kobsd=5.4E-3 h-1, 37 deg C).Deuterium incorporation into the 5-pro-S position of 1 is also observed; pro-S exchange, however, occurs considerably more slowly (kobsd=4.8E-4 h-1, 37 deg C) than does pro-R exchange.Stereoselective exchange was also seen for methyl (S)-dihydroorotate (6) and for 6-methyl-(R,S)-dihydrouracil (7), athough these reactions are only modestly stereopreferential.We have capitalized on this stereochemical preference for 5-pro-R hydrogen exchange by preparing two diastereomers of deuterium-enriched dihydroorotates, 3 (from 1 in D2O buffer) and 5 (from (S)-dihydroorotate 4 in H2O buffer).These chirally deuterated dihydroorotates were used to elucidate the stereochemical course of the reaction (1->2) catalyzed by the beef liver mitochondrial dihydroorotate dehydrogenase (EC 1.3.3.1).Enzymatic oxidation was readily followed by high-field (1)H NMR spectrometry; the data show that the enzyme is absolutely stereoselective with reference to the diastereotopic C5 center.Only the pro-S hydrogen (or deuteron) is lost from C5 during conversion of dihydroorotate to orotate, thereby describing a trans oxidation of substrate.Thus, we report the interesting observation that enzymatic processing of dihydroorotate (1->2) shows stereoselectivity at C5 opposite to that of the nonenzymatic C5-hydrogen exchange (1->3).These results are examined with reference to the conformational, stereoelectronic, and electrostatic factors that may influence the stereochemical course of both the enzyme-catalyzed and nonenzymatic reactions.

Preparation method of vitamin B13

The invention provides a preparation method of vitamin B13. The preparation method specifically comprises the following steps: step 1, carrying out ammonolysis reaction on maleic anhydride and urea toprepare an ammonolysis product; and step 2, oxidizing the ammonolysis product prepared in the step 1 under the catalysis of a catalyst to obtain vitamin B13. The method is a novel chemical reaction,and under the condition that liquid bromine is not used, the ammonolysis product of maleic anhydride and urea can be efficiently converted into vitamin B13. The method has the advantages of simple operation, cheap and easily available reagents, greenness, safety, high efficiency and environmental protection, and is suitable for industrial production.

Synthetic method of orotic acid

The invention discloses a synthetic method of orotic acid, belonging to the technical field of chemical synthesis. The synthetic method of orotic acid comprises the following steps: reacting maleylurea with bromine, wherein the bromine is provided by a reaction of sodium bromide and hydrogen peroxide; and after a reaction of the hydrogen peroxide, the sodium bromide and the maleylurea is finished,adding strong alkali, and adding concentrated hydrochloric acid for acidification after the reaction is completed at 62-64 DEG C so as to obtain the orotic acid. According to the method, the hydrogenperoxide is used for oxidizing the sodium bromide, so elemental halogen used in an original process is replaced, and risks are greatly reduced; the method of applying intermediate bromine generated in situ to a reaction is adopted, so the reaction is uniform and mild, yield and product quality are improved, and the complexity of a production process is reduced; the sodium bromide can be recycled,so no hazardous waste is discharged; in the reaction of synthesizing the maleylurea, acetic acid can be distilled out through reduced-pressure distillation, so cyclic utilization of the acetic acid is achieved, and emission is reduced; and meanwhile, due to process improvement, the yield of the orotic acid is increased.

A orotic improved synthesis method

The present invention discloses an improved synthesis of orotic method, which belongs to the field of organic chemical synthesis, Hein, chloroacetic acid and sodium hydroxide aqueous solution in particular in a microchannel reactor heating reaction to obtain a crude product of orotic, refining the crude product obtained after the pure orotic. The whole production process is carried out in a microchannel reactor, improves the reaction conversion and yield, the reaction yield of 90% or more.

New synthesis method of orotic acid

The invention belongs to the field of organic chemistry and discloses a new synthesis method of orotic acid, comprising the following steps: S1: enabling glycolonitrile and ammonia wate to react, thusobtaining a reaction system a in which a product is aminoacetonitrile A; S2: enabling aminoacetonitrile A and cyanate to react, thus obtaining a reaction system b in which a product is cyanomethylurea B; S3: performing condensation-rearrangement on cyanomethylurea B and glyoxylic acid in an alkaline solution to obtain orotic acid I. The method has the advantages of safe operation, low cost, lesspollution from three wastes, total reaction yield of 80% or above, and easy industrialization.

Novel technology with introduced catalyst to optimize synthesis of dipyridamole

The invention discloses a novel technology with an introduced catalyst to optimize the synthesis of dipyridamole, and belongs to the technical field of medical intermediates. According to the technology, in the step of oxidizing a methyl group of 6-methyl uracil into formic acid, a Co(OAc)2/HOAc/AIBN/O2 catalytic system is introduced, and the reaction yield is increased to 90 to 95%. In the step of reducing a nitro group of nitro-orotic acid into an amino group, activated copper powder is taken as the catalyst, the yield is more than 85%; and moreover, the environmental pollution and danger caused by sodium hydrosulfite are avoided. In the step of converting substituted hydroxyl group into substituted chlorine, SOCl12 and N,N-dimethyl formamide are introduced into the reaction system so as to reduce the environment pollution and the difficulty of post treatment. In the reactions of preparing 2,6-dichloro-4,8-bis(piperidine-1-yl)pyrimido[5,4-d]pyrimidine from perchloro pyrimido[5,4-d]pyrimidine, a CuI/PhNO2 catalytic system is introduced into the reaction system, the reaction yield reaches 95%, moreover, the operation is easy, and the treatment is simple. The provided technology increases the yield, reduces the cost, guarantees the safety, saves the energy, and meets the requirements of green reactions and modern chemical production.