2945-08-6Relevant articles and documents
SUBSTITUTED IMIDAZOLECARBOXAMIDE AS BRUTON'S TYROSINE KINASE INHIBITORS
-
Page/Page column 66-67, (2021/06/11)
The disclosure relates to a series of substituted imidazolecarboxamide compounds of formula I as BTK (Bruton's Tyrosine Kinase) inhibitors, and the methods of using the same for the treatment of autoimmune disease, inflammatory disease, cancer and potenti
Synthesis, biological evaluation and structure-activity relationship of novel dichloroacetophenones targeting pyruvate dehydrogenase kinases with potent anticancer activity
Xu, Biao,Wang, Zhi-Peng,Liu, Qingwang,Yang, Xiaohong,Li, Xuemin,Huang, Ding,Qiu, Yanfei,Tam, Kin Yip,Zhang, Shao-Lin,He, Yun
, (2021/02/09)
Pyruvate dehydrogenase kinases (PDKs) are promising therapeutic targets that have received increasing attentions in cancer metabolism. In this paper, we report the synthesis and biological evaluation of a series of novel dichloroacetophenones as potent PDKs inhibitors. Structure-activity relationship analysis enabled us to identify a potent compound 6u, which inhibited PDKs with an EC50 value of 0.09 μM, and reduced various cancer cells proliferation with IC50 values ranging from 1.1 to 3.8 μM, while show weak effect against non-cancerous L02 cell (IC50 > 10 μM). In the A375 xenograft model, 6u displayed an obvious antitumor activity at a dose of 5 mg/kg, but with no negative effect to the mice weight. Molecular docking suggested that 6u formed direct hydrogen bond interactions with Ser75 and Gln61 in PDK1, and meanwhile the aniline skeleton in 6u was sandwiched by the conserved hydrophobic residues Phe78 and Phe65, which contribute to the biochemical activity improvement. Moreover, 6u induced A375 cell apoptosis and cell arrest in G1 phase, and inhibited cancer cell migration. In addition, 6u altered glucose metabolic pathway in A375 cell by decreasing lactate formation and increasing ROS production and OCR consumption, which could serve as a potential modulator to reprogram the glycolysis pathway in cancer cell.
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
Preparation method of methyl p-aminophenylacetate
-
Paragraph 0056; 0057; 0058; 0059, (2019/01/14)
An embodiment of the invention provides a preparation method of methyl p-aminophenylacetate and relates to the field of chemical synthesis. According to the preparation method, benzyl cyanide is adopted as a starting material and subjected to nitration, hydrolysis, esterification, reduction and other steps in sequence, and methyl p-aminophenylacetate is obtained with high yield. The preparation method adopts a reasonable route, is simple to operate, does not have quite high requirement for equipment and is suitable for large-scale industrial production, and the raw material is widely sourced.
Rational design of novel irreversible inhibitors for human arginase
Guo, Xuefeng,Chen, Yiming,Seto, Christopher T.
, p. 3939 - 3946 (2018/06/19)
Parasites have developed a variety of strategies for invading hosts and escaping their immune response. A common mechanism by which parasites escape nitric oxide (NO) toxicity is the activation of host arginase. This activation leads to a depletion of L-arginine, which is the substrate for NO synthase, resulting in lower levels of NO and increased production of polyamines that are necessary for parasite growth and differentiation. For this reason, small molecule inhibitors for arginase show promise as new anti-parasitic chemotherapeutics. However, few arginase inhibitors have been reported. Here, we describe the discovery of novel irreversible arginase inhibitors, and their characterization using biochemical, kinetic, and structural studies. Importantly, we determined the site on human arginase that is labeled by one of the small molecule inhibitors. The tandem mass spectra data show that the inhibitor occupies the enzyme active site and forms a covalent bond with Thr135 of arginase. These findings pave the way for the development of more potent and selective irreversible arginase inhibitors.
BTK INHIBITOR
-
Paragraph 0359-0360, (2017/11/16)
Provided are a series of BTK inhibitors, and specifically disclosed are a compound, pharmaceutically acceptable salt thereof, tautomer thereof or prodrug thereof represented by formula (I), (II), (III) or (IV).
Photochemical intramolecular amination for the synthesis of heterocycles
Parisien-Collette, Shawn,Cruché, Corentin,Abel-Snape, Xavier,Collins, Shawn K.
supporting information, p. 4798 - 4803 (2017/10/23)
Polycyclic heterocycles can be formed in good to excellent yields via photochemical conversion of the corresponding substituted aryl azides under irradiation with purple LEDs in a continuous flow reactor. The experimental set-up is tolerant to UV-sensitive functional groups while affording diverse carbazoles, as well as an indole and pyrrole framework, in short reaction times. The photochemical method is presumed to progress through a mechanism differing from the other methods of azide activation involving transition metal catalysis.
An Efficient One–pot Procedure for the Direct Preparation of 4,5-Dihydroisoxazoles from Amides
Slagbrand, Tove,Kervefors, Gabriella,Tinnis, Fredrik,Adolfsson, Hans
supporting information, p. 1990 - 1995 (2017/06/09)
A Mo(CO)6 (molybdenumhexacarbonyl) catalyzed reductive functionalization of amides to afford 5-amino substituted 4,5-dihydroisoxazoles is presented. The reduction of amides generates reactive enamines, which upon the addition of hydroximinoyl chlorides and base undergoes a 1,3-dipolar cycloaddition reaction that gives access to the desired heterocyclic compounds. The transformation of amides is highly chemoselective and tolerates functional groups such as nitro, nitriles, esters, and ketones. Furthermore, a versatile scope of 4,5-dihydroisoxazoles derived from a variety of hydroximinoyl chlorides and amides is demonstrated. (Figure presented.).
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).
Preparation method of 4-(3-piperidino) aniline and tartrate thereof
-
Paragraph 0028; 0029, (2017/07/22)
The invention belongs to the field of organic synthesis and particularly relates to a preparation method of 4-(3-piperidino) aniline and tartrate thereof. The preparation method is characterized by comprising the following steps: taking p-nitrophenylaceti
