10268-12-9Relevant articles and documents
Structure-Enabled Discovery of Novel Macrocyclic Inhibitors Targeting Glutaminase 1 Allosteric Binding Site
Xu, Xi,Wang, Jubo,Wang, Min,Yuan, Xinyu,Li, Lei,Zhang, Chao,Huang, Huidan,Jing, Tian,Wang, Chenchen,Tong, Chao,Zhou, Liwen,Meng, Ying,Xu, Pengfei,Kou, Junping,Qiu, Zhixia,Li, Zhiyu,Bian, Jinlei
, p. 4588 - 4611 (2021)
The inhibition of glutaminase 1 (GLS1) represents a potential treatment of malignant tumors. Structural analysis led to the design of a novel series of macrocyclic GLS1 allosteric inhibitors. Through extensive structure-activity relationship studies, a promising candidate molecule 13b (LL202) was identified with robust GLS1 inhibitory activity (IC50 = 6 nM) and high GLS1 binding affinity (SPR, Kd = 24 nM; ITC, Kd = 37 nM). The X-ray crystal structure of the 13b-GLS1 complex was resolved, revealing a unique binding mode and providing a novel structural scaffold for GLS1 allosteric inhibitors. Importantly, 13b clearly adjusted the cellular metabolites and induced an increase in the ROS level by blocking glutamine metabolism. Furthermore, 13b exhibited a similar in vivo antitumor activity as CB839. This study adds to the growing body of evidence that macrocyclization provides an alternative and complementary approach for the design of small-molecule inhibitors, with the potential to improve the binding affinity to the targets.
Nitric acid in dichloromethane solution. Facile preparation from potassium nitrate and sulfuric acid
Strazzolini, Paolo,Giumanini, Angelo G.,Runcio, Antonio
, p. 1387 - 1389 (2001)
Pure dry HNO3 can be liberated from KNO3 with 96% H2SO4 directly into CH2Cl2 to yield solutions of variable concentration for use in a number of organic reactions. The present method efficiently replaces the employment of 100% HNO3 in some synthetic applications, avoiding the problems associated in storage and handling the acid.
Orientation Effect of Side Chain Substituents in Aromatic Substitution. Induced Ortho Nitration
Strazzolini, Paolo,Verardo, Giancarlo,Gorassini, Fausto,Giumanini, Angelo G.
, p. 1155 - 1161 (1995)
The presence of a free carboxyl or ester function on the α-carbon of toluene induces the nitration of the phenyl ring in the ortho position at or above the statistical value (chaperon effect), when pure HNO3 is used in CH2Cl2 solution.This is at variance with the results of classical nitration in H2SO4, where p-nitration predominates by far and m-nitration occurs at a remarkable extent.The new finding is explained in terms of precomplex formation.
Macrocyclic glutaminase GLS1 inhibitor or pharmaceutically acceptable salt thereof and preparation method and application thereof
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, (2020/08/02)
The invention relates to the field of biological medicine, in particular to a series of macrocyclic glutaminase inhibitors, a synthesis method and medical application thereof, and particularly relatesto prevention or treatment of glutaminase related diseases. Meanwhile, the inventor performs a series of in-vitro anti-tumor activity evaluation on the synthesized compounds, and particularly, most of the compounds have good inhibitory activity on cancer cells.
2-Arylamino-6-ethynylpurines are cysteine-targeting irreversible inhibitors of Nek2 kinase
Bayliss, Richard,Boxall, Kathy,Carbain, Benoit,Coxon, Christopher R.,Fry, Andrew M.,Golding, Bernard T.,Griffin, Roger J.,Hardcastle, Ian R.,Harnor, Suzannah J.,Mas-Droux, Corine,Matheson, Christopher J.,Newell, David R.,Richards, Mark W.,Sivaprakasam, Mangaleswaran,Turner, David,Cano, Céline
supporting information, p. 707 - 731 (2020/08/24)
Renewed interest in covalent inhibitors of enzymes implicated in disease states has afforded several agents targeted at protein kinases of relevance to cancers. We now report the design, synthesis and biological evaluation of 6-ethynylpurines that act as covalent inhibitors of Nek2 by capturing a cysteine residue (Cys22) close to the catalytic domain of this protein kinase. Examination of the crystal structure of the non-covalent inhibitor 3-((6-cyclohexylmethoxy-7H-purin-2-yl)amino)benzamide in complex with Nek2 indicated that replacing the alkoxy with an ethynyl group places the terminus of the alkyne close to Cys22 and in a position compatible with the stereoelectronic requirements of a Michael addition. A series of 6-ethynylpurines was prepared and a structure activity relationship (SAR) established for inhibition of Nek2. 6-Ethynyl-N-phenyl-7H-purin-2-amine [IC50 0.15 μM (Nek2)] and 4-((6-ethynyl-7H-purin-2-yl)amino)benzenesulfonamide (IC50 0.14 μM) were selected for determination of the mode of inhibition of Nek2, which was shown to be time-dependent, not reversed by addition of ATP and negated by site directed mutagenesis of Cys22 to alanine. Replacement of the ethynyl group by ethyl or cyano abrogated activity. Variation of substituents on the N-phenyl moiety for 6-ethynylpurines gave further SAR data for Nek2 inhibition. The data showed little correlation of activity with the nature of the substituent, indicating that after sufficient initial competitive binding to Nek2 subsequent covalent modification of Cys22 occurs in all cases. A typical activity profile was that for 2-(3-((6-ethynyl-9H-purin-2-yl)amino)phenyl)acetamide [IC50 0.06 μM (Nek2); GI50 (SKBR3) 2.2 μM] which exhibited >5-10-fold selectivity for Nek2 over other kinases; it also showed > 50% growth inhibition at 10 μM concentration against selected breast and leukaemia cell lines. X-ray crystallographic analysis confirmed that binding of the compound to the Nek2 ATP-binding site resulted in covalent modification of Cys22. Further studies confirmed that 2-(3-((6-ethynyl-9H-purin-2-yl)amino)phenyl)acetamide has the attributes of a drug-like compound with good aqueous solubility, no inhibition of hERG at 25 μM and a good stability profile in human liver microsomes. It is concluded that 6-ethynylpurines are promising agents for cancer treatment by virtue of their selective inhibition of Nek2. This journal is
SUBSTITUTED N-HYDROXYAMIDINOHETEROCYCLES AS MODULATORS OF INDOLEAMINE 2,3- DIOXYGENASE
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Page/Page column 52, (2018/05/24)
The invention provides modulators of indoleamine 2,3-dioxygenase (IDO1) and their use in the prophylaxis and/or treatment of IDO1-mediated diseases. Specifically, the present invention provides compounds according to Formula (I) an enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof.
Antiproliferative activity and SARs of caffeic acid esters with mono-substituted phenylethanols moiety
Xie, Jin,Yang, Fengzhi,Zhang, Man,Lam, Celine,Qiao, Yixue,Xiao, Jia,Zhang, Dongdong,Ge, Yuxuan,Fu, Lei,Xie, Dongsheng
supporting information, p. 131 - 134 (2016/12/27)
A series of CAPE derivatives with mono-substituted phenylethanols moiety were synthesized and evaluated by MTT assay on growth of 4 human cancer cell lines (Hela, DU-145, MCF-7 and ECA-109). The substituent effects on the antiproliferative activity were systematically investigated for the first time. It was found that electron-donating and hydrophobic substituents at 2′-position of phenylethanol moiety could significantly enhance CAPE's antiproliferative activity. 2′-Propoxyl derivative, as a novel caffeic acid ester, exhibited exquisite potency (IC50?=?0.4?±?0.02 & 0.6?±?0.03?μM against Hela and DU-145 respectively).
BORONIC ACID DERIVATIVES
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Page/Page column 96; 97, (2016/04/26)
Compounds of formula (I) are inhibitors of LMP7 and can be employed, inter alia, for the treatment of an autoimmue disorder abnomality or hematological malignancies.
Visible-Light-Induced Meerwein Cascade Reactions for the Preparation of α-Aryl Esters
Niu, Teng-Fei,Li, Liang,Ni, Bang-Qing,Bu, Mei-Jie,Cai, Chun,Jiang, Hui-Liang
, p. 5775 - 5780 (2015/09/15)
A practical strategy has been developed for preparation of α-aryl ester derivatives by using a visible-light-induced Meerwein cascade reaction. This method uses molecular oxygen as an oxidant at room temperature without the need of hazardous reagents or harsh reaction conditions and provides a straightforward approach to pharmaceutically and synthetically useful α-aryl esters in moderate to good yields from simple and readily available starting materials. Oxindoles were also prepared by this protocol. A new strategy for the synthesis of α-aryl esters has been reported. This protocol utilizes acrylonitrile as a "bridge molecule" to combine a visible-light-induced Meerwein reaction and a hydrolysis reaction to generate α-aryl esters. This method was also employed for the preparation of oxindoles.
INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL
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Page/Page column 96, (2014/07/08)
The present invention provides compounds of Formula I and the pharmaceutically acceptable salts thereof, which are inhibitors of the ROMK (Kirl.1) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophylaxis of medical conditions including cardiovascular diseases such as hypertension, heart failure and conditions associated with excessive salt and water retention.
