- Introducing a potential lead structure for the synthesis of more specific inhibitors of tyrosinases and catechol oxidases
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Based on tyrosinase inhibition science, two pyrimidine derivatives were designed and studied. Docking of 2-dibenzylamine-5-hydroxy pyrimidine (dba5HP) and 2-benzylamino-5-hydroxy pyrimidine (ba5HP) on mushroom tyrosinase (MT) showed that the former could not occupy MT active site pocket, while ba5HP could do so (Moldock score = ? 63.95). MD simulation revealed that the complex of ba5HP-MT reached stability 50 = 32.28, Ki = 11.32?μM). Considering the facile synthesis, potential for structural modifications, and passing most of the lead-likeness filters, it seems likely that ba5HP plays key roles in the syntheses of novel depigmentation medicines as well as more specific inhibitors for various tyrosinases and polyphenol oxidases.
- Amirzakaria, Javad Zamani,Eshghi, Hossein,Ghorbanian, Nargess,Haghbeen, Faheimeh,Haghbeen, Kamahldin,Hajatpour, Golnaz
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- Discovery of (R)-5-((5-(1-methyl-1H-pyrazol-4-yl)-4-(methylamino)pyrimidin-2-yl)amino)-3-(piperidin-3-yloxy)picolinonitrile, a novel CHK1 inhibitor for hematologic malignancies
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Through virtual screening, we identified the lead compound MCL1020, which exhibited modest CHK1 inhibitory activity. Then a series of 5-(pyrimidin-2-ylamino)picolinonitrile derivatives as CHK1 inhibitors were discovered by further rational optimization. One promising molecule, (R)-17, whose potency was one of the best, had an IC50 of 0.4 nM with remarkable selectivity (>4300-fold CHK1 vs. CHK2). Compound (R)-17 effectively inhibited the growth of malignant hematopathy cell lines especially Z-138 (IC50: 0.013 μM) and displayed low affinity for hERG (IC50 > 40 μM). Moreover, (R)-17 significantly suppressed the tumor growth in Z-138 cell inoculated xenograft model (20 mg/kg I.V., TGI = 90.29%) as a single agent with body weight unaffected. Taken together, our data demonstrated compound (R)-17 could be a promising drug candidate for the treatment of hematologic malignancies.
- Tong, Lexian,Song, Pinrao,Jiang, Kailong,Xu, Lei,Jin, Tingting,Wang, Peipei,Hu, Xiaobei,Fang, Sui,Gao, Anhui,Zhou, Yubo,Liu, Tao,Li, Jia,Hu, Yongzhou
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- Proton Sensitive Functional Organic Fluorescent Dyes Based on Coumarin-imidazo[1,2-a]pyrimidine; Syntheses, Photophysical Properties, and Investigation of Protonation Ability
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A novel series of 2-coumarin-3-yl-imidazo[1,2-a]pyrimidines have been synthesized with functionalized coumarin and pyrimidine units of the different architecture to give various fluorescent compounds. A new additional series bearing unsubstituted coumarin and 7-dialkylaminocoumarin as fluorophore were obtained by palladium-catalyzed cross-coupling reactions, through coupling of 6-bromo-2-coumarin-3-yl-imidazopyrimidine derivatives with various arylboronic acids. In the all reaction step, microwave irradiation (MWI) method was used and compared with the conventional method (CM). Photophysical properties of synthesized compounds were studied by a combination of UV/Vis and fluorescence spectroscopy in various solvents having different polarities. The protonation abilities of all compounds were investigated by titration with trifluoroacetic acid (TFA) in dichloromethane. In both series, the compounds bearing 7-dialkylaminocoumarin are fluorescently active even in daylight and showed maximum absorption wavelengths (λabs–max) in the visible region in all solvents used. In addition, they showed drastic color and emission change in acidic environment. Moreover, for the investigation of protonation ability of three selected compounds bearing 7-dialkylaminocoumarin have been studied using a buffer solution with various pH and determinated their pKa values. The compound bearing morpholine has the potential to use as colorimetric and luminescence pH sensor. The thermal properties of all the synthesized compounds were also evaluated with TGA to test their usability as optic dyes.
- Ayd?ner, Burcu,Sefero?lu, Zeynel
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p. 5921 - 5934
(2018/11/23)
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- 2-polysubstituted aromatic ring-pyrimidine derivative and preparation and medical application
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The invention provides a 2-polysubstituted aromatic ring-pyrimidine derivative, an optical isomer of the derivative or a medically acceptable salt or solvate of the derivative, and application of the compound, the optical isomer of the derivative or the medically acceptable salt or solvate of the derivative in preparing antineoplastic medicine. According to the 2-polysubstituted aromatic ring-pyrimidine derivative, by adopting N-substituted pyridine-2-minopyrimidine as a lead compound obtained based on virtual screening of a structure, a series of brand new small molecule Chk1 inhibitors are designed and synthesized, and a Chk1 kinase inhibitory activity test of a molecular level is conducted on the compound. Experiments prove that the compound is a Chk1 inhibitor with a strong antitumous effect, Chk1 kinase inhibitory activity and a prospect, and new cancer treating medicine, and can be used for treating solid tumor or leukemia related with human or animal cell proliferation. The 2-polysubstituted aromatic ring-pyrimidine derivative has a structure shown in the general formula I.
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Paragraph 0210; 0214; 0215; 0216
(2017/05/20)
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- IF5 affects the final stage of the Cl-F exchange fluorination in the synthesis of pentafluoro-λ6-sulfanyl-pyridines, pyrimidines and benzenes with electron-withdrawing substituents
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A difficult chlorine-fluorine (Cl-F) exchange fluorination reaction in the final stage of the preparation of pentafluoro-λ6-sulfanyl-(hetero)arenes having electron-withdrawing substituents has now been elucidated through the use of iodine pentafluoride. A major side-reaction of C-S bond cleavage was sufficiently inhibited by the potential interaction between F and I with a halogen bonding.
- Cui, Benqiang,Kosobokov, Mikhail,Matsuzaki, Kohei,Tokunaga, Etsuko,Shibata, Norio
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supporting information
p. 5997 - 6000
(2017/07/10)
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- pyrimidine derivatives substituted with aryl- or heteroaryl- substituted fluorene group, and organic electroluminescent device including the same
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Aryl group or a heteroaryl group substituted pyrimidine derivatives of formula 1 is coupled to polyarylenic backbone containing encoded ball number. [Formula 1] [In said formula 1, Ar1 And Ar2 Are each independently a hydrogen, methyl or phenyl, The C L6 - C24 C aryl of reflector3 - C24 It will be biting and heteroatoms, N is an integer 0 or 1 and, Ar3 The C6 - C30 C aryl of reflector3 - C30 A variety of printers] (by machine translation)
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Paragraph 0118; 0119; 0120; 0121
(2017/10/28)
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- Synthesis method of 2-amino-5-bromopyrimidine
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The invention relates to a synthesis method of 2-amino-5-bromopyrimidine. The 2-aminopyrimidine and N-bromo-succinimide are used as raw materials; the mol ratio of the 2-aminopyrimidine to the N-bromo-succinimide is 1: (0.65 to 2.3); the mol ratio of the 2-aminopyrimidine to a solvent is 1:(2.0 to 11); in a proper solvent, the reaction is continuously performed for 3 to 15 hours at 35 to 110 DEG C to produce a coarse product of 2-amino-5-bromopyrimidine; through recrystallization, a pure product of the 2-amino-5-bromopyrimidine is obtained. The raw materials can be easily obtained; the price is reasonable; meanwhile, heavy metal and corrosion gas are not used in the preparation reaction; the reaction is mild; no special requirements exist on the reaction equipment; the production can be performed by using ordinary anti-corrosion equipment; the reaction yield is high; the purity is high.
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Paragraph 0011; 0012; 0013; 0014; 0015; 0016
(2017/08/28)
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- KINASE INHIBITOR AND USE THEREOF
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The invention relates to a CDK4/6 kinase inhibitor, or a pharmaceutically acceptable salt, ester, or solvate thereof, or their isomers; a pharmaceutical formulation, pharmaceutical composition and kit comprising said CDK4/6 kinase inhibitor, or a pharmaceutically acceptable salt, ester, or solvate thereof, or their isomers, and use of said CDK4/6 kinase inhibitor, or a pharmaceutically acceptable salt, ester, or solvate thereof, or their isomers. For example, the compounds of the invention are useful for reducing or inhibiting the activity of CDK4/6 kinase in a cell, and/or treating and/or preventing a cancer-related disease mediated by CDK4/6 kinase.
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Paragraph 0183; 0184
(2016/11/21)
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- A quick, mild and efficient bromination using a CFBSA/KBr system
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Bromination is a fundamental transformation in organic chemistry and brominated compounds as building blocks are of paramount importance in organic synthesis. In our study, we have developed an efficient method of bromination by using a CFBSA/KBr system at room temperature in a short reaction time. Notably, this approach has been proven to be applicable to a range of substrates including 1,3-diketones and β-keto esters, phenols, aromatic amines and heteroarenes with good to excellent yields.
- Jiang, Pan-Pan,Yang, Xian-Jin
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p. 90031 - 90034
(2016/10/09)
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- Synthesis and biological evaluation of glucagon-like peptide-1 receptor agonists
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In this study, a series of fused-heterocyclic derivatives were systematically designed and synthesized using an efficient route, and evaluated in terms of GLP-1R agonist activity. We employed short synthetic steps and reactions that are tolerant of the presence of various functional groups and suitable for parallel operations to enable the rapid generation of libraries of diverse and structurally complex small molecules. Of the compounds synthesized, 3-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a] pyridin-2-yl)phenyl methanesulfonate (8e) was the most potent agonist with an EC50 of 7.89 μM, and thus is the compound with the greatest potential for application. These findings represent a valuable starting point for the design and discovery of small-molecule GLP-1R agonists that can be administered orally.
- Zhang, Yu-Juan,Shen, Liu-Lan,Cheon, Hyae-Gyeong,Xu, Yong-Nan,Jeong, Jin-Hyun
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p. 588 - 599
(2014/06/09)
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- Design, synthesis, and biological evaluation of 3-(1H-1,2,3-triazol-1-yl) benzamide derivatives as potent pan Bcr-Abl inhibitors including the threonine315←isoleucine315 mutant
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A series of 3-(1H-1,2,3-triazol-1-yl)benzamide derivatives were designed and synthesized as new Bcr-Abl inhibitors by using combinational strategies of bioisosteric replacement, scaffold hopping, and conformational constraint. The compounds displayed significant inhibition against a broad spectrum of Bcr-Abl mutants including the gatekeeper T315I and p-loop mutations, which are associated with disease progression in CML. The most potent compounds 6q and 6qo strongly inhibited the kinase activities of Bcr-AblWT and Bcr-AblT315I with IC50 values of 0.60, 0.36 and 1.12, 0.98 nM, respectively. They also potently suppressed the proliferation of K562, KU812 human CML cells, and a panel of murine Ba/F3 cells ectopically expressing either Bcr-AblWT or any of a panel of other Bcr-Abl mutants that have been shown to contribute to clinical acquired resistance, including Bcr-AblT315I, with IC50 values in low nanomolar ranges. These compounds may serve as lead compounds for further development of new Bcr-Abl inhibitors capable of overcoming clinical acquired resistance against imatinib.
- Li, Yupeng,Shen, Mengjie,Zhang, Zhang,Luo, Jinfeng,Pan, Xiaofen,Lu, Xiaoyun,Long, Huoyou,Wen, Donghai,Zhang, Fengxiang,Leng, Fang,Li, Yingjun,Tu, Zhengchao,Ren, Xiaomei,Ding, Ke
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p. 10033 - 10046
(2013/01/16)
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- SUBSTITUTED DIARYLAMINES AND USE OF SAME AS ANTIOXIDANTS
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The present invention relates to substituted heteroaromatic dianlamine compounds of Formula I and II, their pharmaceutically acceptable salts, and compositions thereof useful as antioxidants, wherein each of X, Y and Z are independently a carbon or nitrogen atom; R1 and R2 are each independently a hydrogen or an electron donating group, but are not both hydrogen, and wherein R1 and R2 are each bonded to a carbon atom in their own respective aryl ring.
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Page/Page column 45
(2013/02/28)
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- Preparation of highly reactive pyridine- and pyrimidine-containing diarylamine antioxidants
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We recently reported a preliminary account of our efforts to develop novel diarylamine radical-trapping antioxidants (Hanthorn, J. J. et al. J. Am. Chem. Soc. 2012, 134, 8306-8309) wherein we demonstrated that the incorporation of ring nitrogens into diphenylamines affords compounds which display a compromise between H-atom transfer reactivity to peroxyl radicals and stability to one-electron oxidation. Herein we provide the details of the synthetic efforts associated with that report, which have been substantially expanded to produce a library of substituted heterocyclic diarylamines that we have used to provide further insight into the structure-reactivity relationships of these compounds as antioxidants (see the accompanying paper, DOI: 10.1021/jo301012x). The diarylamines were prepared in short, modular sequences from 2-aminopyridine and 2-aminopyrimidine wherein aminations of intermediate pyri(mi)dyl bromides and then Pd-catalyzed cross-coupling reactions of the amines and precursor bromides were the key steps to yield the diarylamines. The cross-coupling reactions were found to proceed best with Pd(η3-1-PhC3H 4)(η5-C5H5) as precatalyst, which gave higher yields than the conventional Pd source, Pd2(dba) 3.
- Hanthorn, Jason J.,Valgimigli, Luca,Pratt, Derek A.
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experimental part
p. 6908 - 6916
(2012/10/08)
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- A simple Cu-catalyzed coupling approach to substituted 3-pyridinol and 5-pyrimidinol antioxidants
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(Chemical Equation Presented) A convenient approach to 3-pyridinols and 5-pyrimidinols via a two-step Cu-catalyzed benzyloxylation/catalytic hydrogenation sequence is presented. The corresponding 3-pyridinamines and 5-pyrimidinamines can be prepared in an analogous sequence utilizing benzylamine in lieu of benzyl alcohol. The radical-scavenging ability of these derivatives are preliminarily explored and reveal that the increased acidities of the pyridinols and pyrimidinols render them susceptible to more significant kinetic solvent effects when compared to phenols.
- Nara, Susheel J.,Jha, Mukund,Brinkhorst, Johan,Zemanek, Tony J.,Pratt, Derek A.
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supporting information; experimental part
p. 9326 - 9333
(2009/04/06)
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- THIOPHENE HETEROARYL AMINES
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The present invention relates to thiophene heteroaryl amines and their pharmaceutically acceptable salts that modulate the activity of protein kinases and therefore are expected to be useful in the prevention and treatment of protein kinase related cellular disorders such as cancer. Formula (I).
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Page/Page column 32
(2010/02/14)
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- [bmim]Br3 as a new reagent for regioselective monobromination of arylamines under solvent-free conditions
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Reaction of arylamines with 1-butyl-3-methylimidazolium tribromide ([bmim]Br3) under solvent-free conditions, gave selectively the corresponding monobromination products with excellent, yields.
- Le, Zhang-Gao,Chen, Zhen-Chu,Hu, Yi,Zheng, Qin-Guo
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p. 2809 - 2812
(2007/10/03)
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- A new mild regioselective bromination of arylamines
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A new efficient regioselective boron-assisted mono bromination methodology for arylamines is described. Our one-pot, three-stage approach (lithiation, boron amide formation and bromination) proved to be highly useful in mildly brominating a variety of arylamines in up to 94% yields.
- Zhao, Jingrui,Jia, Xueshun,Zhai, Hongbin
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p. 9371 - 9373
(2007/10/03)
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- Regioselective one-pot bromination of aromatic amines
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(Matrix Presented) Treatment of aniline with n-butyllithium and then trimethyltin chloride gave the tin amide (PhNH-SnMe3) in situ. Without isolation of the tin amide reaction with bromine and workup with aqueous fluoride ion gave p-bromoaniline in 76% yield, with no dibromoaniline or o-bromoaniline. Application of this sequence to 11 different aromatic amines gave selective bromination in 36-91% yields, without formation of dibromides. This constitutes a good general method for the regioselective bromination of aromatic amines.
- Smith, Michael B.,Guo, Lisa,Okeyo, Sherrad,Stenzel, Jason,Yanella, James,LaChapelle, Eric
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p. 2321 - 2323
(2007/10/03)
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- Synthesis, transition temperatures, and optical properties of compounds with simple phenyl units linked by double bond, triple bond, ester or propiolate linkages
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A series of compounds has been prepared with 4-butylsulfanylphenyl and 4-cyano- or 4-isothiocyanato-phenyl units connected by -CH=CH-, -COO-, -C≡C- , or -C≡C-COO- linking groups. The synthesis of the novel compounds is presented and the transition temperatures and optical parameters of the compounds are discussed and compared with those for related biphenyl reference systems. The ester linking group reduces optical and polarisability anisotropy, but the other linking groups give increased optical anisotropy (up to Δn = 0.50) and polarisability anisotropy [up to Δα = 45.2 A3 (10-30 m3)].
- Cross, Gregory J.,Seed, Alexander J.,Toyne, Kenneth J.,Goodby, John W.,Hird, Michael,Artal, M. Carmen
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p. 1555 - 1563
(2007/10/03)
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- DIAZOTIZATION OF SOME AMINODIAZINE N-OXIDES
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Diazotization of a number of aminopyrazine and aminopyrimidine N-oxides affords intermediate diazonium compounds which can be converted to the corresponding bromo and chloro analogs in the presence of the appropriate halide ions.In some instances, electrophilic aromatic substitution takes place prior to the diazotization step.Nucleophilic halogenation accompanying deoxygenation occurs with 2-aminopyrimidine N-oxide in the same manner as described for some 3-amino-1,2,4-triazine 2-oxides.
- Jovanovic, Misa V.
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p. 2011 - 2018
(2007/10/02)
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- Bromination of Some Pyridine and Diazine N-Oxides
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Selected monosubstituted pyridines, pyrazines, pyrimidines, and their N-oxides, having an electron-donating substituent, were successfully brominated under very mild conditions.The N-oxide function itself is not sufficient to cause these ?-deficient systems to undergo electrophilic aromatic halogenation.Only strongly electron-donating substituents (amino groups) activate the heterocyclic nucleus toward bromination.These substituents direct the electrophilic substitution ortho/para to them with or without the N-oxide group present.Pyridine and diazines with moderately activating substituents such as alkoxy groups are brominated only when their ortho/para activation is augmented by the activation of the N-oxide funtion.Failure to brominate 5-methoxypyrimidine 1-oxide may well reflect the greater ? deficiency of the pyrimidine ring.
- Paudler, William W.,Jovanovic, Misa V.
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p. 1064 - 1069
(2007/10/02)
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