366-84-7Relevant articles and documents
Discovery of a Potent Glutathione Peroxidase 4 Inhibitor as a Selective Ferroptosis Inducer
Xu, Congjun,Xiao, Zhanghong,Wang, Jing,Lai, Hualu,Zhang, Tao,Guan, Zilin,Xia, Meng,Chen, Meixu,Ren, Lingling,He, Yuanfeng,Gao, Yuqi,Zhao, Chunshun
, p. 13312 - 13326 (2021/09/28)
Potent and selective ferroptosis regulators promote an intensive understanding of the regulation and mechanisms underlying ferroptosis, which is highly associated with various diseases. In this study, through a stepwise structure optimization, a potent and selective ferroptosis inducer was developed targeting to inhibit glutathione peroxidase 4 (GPX4), and the structure-activity relationship (SAR) of these compounds was uncovered. Compound26aexhibited outstanding GPX4 inhibitory activity with a percent inhibition up to 71.7% at 1.0 μM compared to 45.9% of RSL-3. At the cellular level,26acould significantly induce lipid peroxide (LPO) increase and effectively induce ferroptosis with satisfactory selectivity (the value of 31.5). The morphological analysis confirmed the ferroptosis induced by26a. Furthermore,26asignificantly restrained tumor growth in a mouse 4T1 xenograft model without obvious toxicity.
HISTONE DEMETHYLASE INHIBITORS FOR TREATING CANCERS
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Paragraph 0178-0179, (2021/01/22)
The present disclosure provides a new series of 8-hydroxyquinoline derivatives/analogs that are potent KDM4 inhibitors with high activity and selectivity against KDM4 enzymes. Also disclosed are the pharmaceutical compositions comprising such 8-hydroxyqui
PTG-0861: A novel HDAC6-selective inhibitor as a therapeutic strategy in acute myeloid leukaemia
Bukhari, Shazreh,Cabral, Aaron D.,Gawel, Justyna M.,Gunning, Patrick T.,Israelian, Johan,Manaswiyoungkul, Pimyupa,Nawar, Nabanita,Olaoye, Olasunkanmi O.,Radu, Tudor B.,Raouf, Yasir S.,Sedighi, Abootaleb,Shouksmith, Andrew E.,Sina, Diana,Toutah, Krimo,de Araujo, Elvin D.
, (2020/07/03)
Dysregulated Histone Deacetylase (HDAC) activity across multiple human pathologies have highlighted this family of epigenetic enzymes as critical druggable targets, amenable to small molecule intervention. While efficacious, current approaches using non-selective HDAC inhibitors (HDACi) have been shown to cause a range of undesirable clinical toxicities. To circumvent this, recent efforts have focused on the design of highly selective HDACi as a novel therapeutic strategy. Beyond roles in regulating transcription, the unique HDAC6 (with two catalytic domains) regulates the deacetylation of α-tubulin; promoting growth factor-controlled cell motility, cell division, and metastatic hallmarks. Recent studies have linked aberrant HDAC6 function in various hematological cancers including acute myeloid leukaemia and multiple myeloma. Herein, we report the discovery, in vitro characterization, and biological evaluation of PTG-0861 (JG-265), a novel HDAC6-selective inhibitor with strong isozyme-selectivity (～36× ) and low nanomolar potency (IC50 = 5.92 nM) against HDAC6. This selectivity profile was rationalized via in silico docking studies and also observed in cellulo through cellular target engagement. Moreover, PTG-0861 achieved relevant potency against several blood cancer cell lines (e.g. MV4-11, MM1S), whilst showing limited cytotoxicity against non-malignant cells (e.g. NHF, HUVEC) and CD-1 mice. In examining compound stability and cellular permeability, PTG-0861 revealed a promising in vitro pharmacokinetic (PK) profile. Altogether, in this study we identified a novel and potent HDAC6-selective inhibitor (～4× more selective than current clinical standards – citarinostat, ricolinostat), which achieves cellular target engagement, efficacy in hematological cancer cells with a promising safety profile and in vitro PK.
P-aminomethyl benzoic acid and preparation method thereof
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Paragraph 0051-0053, (2020/09/09)
The invention discloses p-aminomethyl benzoic acid and a preparation method thereof. The method comprises the following steps: hydrolyzing phthalic anhydride as a raw material under an alkaline condition to enable the anhydride structure of phthalic anhydride to be subjected to ring opening to obtain an intermediate 1; performing decarboxylation reaction on the intermediate 1 under the condition that high-temperature liquid water is used as a reaction medium to obtain an intermediate 2; converting original binary acid of the intermediate 1 into monobasic acid, and enabling the intermediate 2 to react with a saturated monochloromethane diethyl ether solution by taking diethyl ether as a solvent under the catalytic action of aluminum chloride to obtain an intermediates 3; and carrying out bromine substitution reaction on the intermediate 3 and N-bromosuccinimide, and carrying out ammoniation reaction under the action of triethylamine and potassium carbonate. The yield of p-aminomethyl benzoic acid prepared by the preparation method of p-aminomethyl benzoic acid is high, and compared with an existing preparation method, most of the used raw materials are low-price raw materials, cyanogroups with high toxicity are not introduced, and the production cost of tranexamic acid is greatly reduced.
Design, synthesis, biological evaluation and molecular dynamics studies of 4-thiazolinone derivatives as protein tyrosine phosphatase 1B (PTP1B) inhibitors
Liu, Wen-Shan,Wang, Rui-Rui,Yue, Hai,Zheng, Zhi-Hui,Lu, Xin-Hua,Wang, Shu-Qing,Dong, Wei-Li,Wang, Run-Ling
, p. 3814 - 3824 (2019/11/03)
Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin signaling pathway, and more and more studies have shown that it is a potential target for the treatment of type 2 diabetes mellitus (T2DM). In this study, 17 new 4-thiazolinone derivatives were designed and synthesized as novel PTP1B inhibitors, and ADMET prediction confirmed that these compounds were to be drug-like. In vitro enzyme activity experiments were performed on these compounds, and it was found that a plurality of compounds had good inhibitory activity and high selectivity against PTP1B protein. Among them, compound 7p exhibited the best inhibitory activity with an IC50 of 0.92 μM. The binding mode of compound 7p and PTP1B protein was explored, revealing the reason for its high efficiency. In addition, molecular dynamics simulations for the PTP1BWT and PTP1Bcomp#7p systems revealed the effects of compound 7p on PTP1B protein at the molecular level. In summary, the study reported for the first time that 4-thiazolinone derivatives as a novel PTP1B inhibitor had good inhibitory activity and selectivity for the treatment of T2DM, providing more options for the development of PTP1B inhibitors. AbbreviationsBBB blood-brain barrierCDC25B cell division cycle 25 homolog BCYP2D6 Cytochrome P450 2D6 bindingDCCM dynamic cross-correlation mapDS Discovery StudioH bond hydrogen bondHIA human intestinal absorptionLAR leukocyte antigen-related phosphataseMD molecular dynamicsMEG-2 maternal-effect germ-cell defective 2MM-PBSA molecular mechanics Poisson Boltzmann surface area)PCA principal component analysisPDB Protein Data BankpNPP p–nitrophenyl phosphatePPB plasma protein bindingPTP1B protein tyrosine phosphotase 1BRMSD root mean square deviationRMSF root mean square fluctuationSHP-1 src homologous phosphatase-1SHP-2 src homologous phosphatase-2SPC single-point chargeTCPTP T cell protein tyrosine phosphataseT2DM Type 2 diabetes mellitusVDW van der Waals Communicated by Ramaswamy H. Sarma.
Platinum-(phosphinito-phosphinous acid) complexes as bi-talented catalysts for oxidative fragmentation of piperidinols: An entry to primary amines
Membrat, Romain,Vasseur, Alexandre,Moraleda, Delphine,Michaud-Chevallier, Sabine,Martinez, Alexandre,Giordano, Laurent,Nuel, Didier
, p. 37825 - 37829 (2019/12/03)
Platinum-(phosphinito-phosphinous acid) complex catalyzes the oxidative fragmentation of hindered piperidinols according to a hydrogen transfer induced methodology. This catalyst acts successively as both a hydrogen carrier and soft Lewis acid in a one pot-two steps process. This method can be applied to the synthesis of a wide variety of primary amines in a pure form by a simple acid-base extraction without further purification.
Well-Defined Amidate-Functionalized N-Heterocyclic Carbene -Supported Rare-Earth Metal Complexes as Catalysts for Efficient Hydroboration of Unactivated Imines and Nitriles
Huang, Zeming,Wang, Shaowu,Zhu, Xiancui,Yuan, Qingbing,Wei, Yun,Zhou, Shuangliu,Mu, Xiaolong
supporting information, p. 15069 - 15078 (2018/12/14)
Four amidate-functionalized N-heterocyclic carbene (NHC) rare-earth metal amido complexes [(κ2-N,O-κ1-L)2REN(SiMe3)2] (L = 1-(C6H5CONCH2CH2)-3-(CH3)3C6H2(N(CH)2NC)) [RE = Er (1), Y (2), Dy (3), Gd (4)] were synthesized by one-pot reactions of 2 equiv of (1-(C6H5CONHCH2CH2)-3-(CH3)3C6H2-(N(CH)2NCH))Br (H2LBr) with 5 equiv of KN(SiMe3)3 followed by treatment with 1 equiv of RECl3 in tetrahydrofuran at -40 °C. These complexes were fully characterized, and their catalytic activities toward hydroboration of unactivated imines and nitriles were investigated, and it was found that these complexes displayed excellent activities as well as remarkable functional group compatibility for imine and nitrile substrates such as halo-, alkyl-, hydroxyl-, N,N-dimethylamino-, and nitro- substituents. Among those, the chemoselectivity for this reaction among the common unsaturated functional groups was achieved in the order CO CN > C=N > CO2Et > CC in the current catalytic system, which may facilitate their further application in synthetic chemistry.
Synthetic method for aminomethylbenzoic acid
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Paragraph 0043; 0044, (2018/11/22)
The invention discloses a synthetic method for aminomethylbenzoic acid. The synthetic method specifically comprises the following steps: adding 4-halomethyl alkyl benzoate and triethylamine, dropwiseadding ethanol-water solution in which 2-amino-5-methyl-1,3,4-thiadiazole is dissolved while stirring, after a reaction is completed, evaporating solution until a lot of solids are separated out, cooling, filtering, and drying to obtain 4-aminomethyl alkyl benzoate; adding the 4-aminomethyl alkyl benzoate to acid solution, reacting by stirring, cooling, adding water, and dropwise adding alkali until the solution is alkaline, and a lot of the solids are separated out, filtering, washing, and drying to obtain the aminomethylbenzoic acid. The synthetic method is moderate in reaction conditions, less in side reactions, high in yield, low in cost, short in reaction and post-processing time, low in energy consumption, high in production efficiency, small in environmental pollution, and simple in'three wastes' treatment, and suitable for the industrial production. -CN with strong toxicity and an organic solvent with strong pollution are not used, and reaction raw materials are cheap in priceand easy to obtain.
Cobalt complex, preparation method thereof, and application thereof in selective catalysis of transfer hydrogenation reaction of cyano group
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Paragraph 0157-0159; 0161, (2018/05/07)
The invention discloses a cobalt complex, a preparation method thereof, and an application thereof in the selective catalysis of a transfer hydrogenation reaction of a cyano group. The structural formula of the cobalt complex is represented by formula I. The cobalt complex is prepared through a reaction of a cobalt salt and an NNP ligand or a PNP ligand under the protection of an inert atmosphere;and the chemical formula of the cobalt salt is CoX12, wherein X1 represents halogen, a sulfate radical, a perchlorate radical, a hexafluorophosphate radical, a hexafluoroantimonate radical, a tetrafluoroborate radical, a trifluoromethanesulfonate radical or a tetra(pentafluorophenyl)borate radical. The cobalt complex can be used in the selective catalysis of the transfer hydrogenation reaction ofthe cyano group to obtain a primary amine compound, a secondary amine compound and a tertiary amine compound, the primary amine compound, the secondary amine compound and the tertiary amine compoundare important intermediates in a series of subsequent functionalizing reactions, and the cobalt complex has a very high catalysis activity, and has great research values and a great application prospect.
Identification of ortho-Substituted Benzoic Acid/Ester Derivatives via the Gas-Phase Neighboring Group Participation Effect in (+)-ESI High Resolution Mass Spectrometry
Blincoe, William D.,Rodriguez-Granillo, Agustina,Saurí, Josep,Pierson, Nicholas A.,Joyce, Leo A.,Mangion, Ian,Sheng, Huaming
, p. 694 - 703 (2018/04/14)
Benzoic acid/ester/amide derivatives are common moieties in pharmaceutical compounds and present a challenge in positional isomer identification by traditional tandem mass spectrometric analysis. A method is presented for exploiting the gas-phase neighbor
