- Discovery of 5,6-Bis(4-methoxy-3-methylphenyl)pyridin-2-amine as a WSB1 Degrader to Inhibit Cancer Cell Metastasis
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The gain of cell motility is an essential prerequisite for cancer metastasis. The ubiquitin ligase subunit WD repeat and SOCS box-containing 1 (WSB1) has been demonstrated to regulate hypoxia-driven tumor cell migration. However, there is still a lack of methods for discovering inhibitors targeting the WSB1 axis. Here, we employed phenotypic screening models and identified compound4that displayed migration inhibitory activity against WSB1-overexpressing cells. Further studies indicated that it may function as a WSB1 degrader, thus leading to the accumulation of the Rho guanosine diphosphate dissociation inhibitor 2 (RhoGDI2) protein, reversing the expression of downstream F-actin and formation of membrane ruffles, and disturbing the migration capacity of cancer cells. Moreover, compound4exhibited a promisingin vivoanticancer metastatic effects. Our findings show the discovery of a new WSB1 degrader, providing a unique solution for the treatment of cancer metastasis.
- Che, Jinxin,Jin, Zegao,Yan, Fangjie,You, Jieqiong,Xie, Jiangfeng,Chen, Binhui,Cheng, Gang,Zhu, Hong,He, Qiaojun,Hu, Yongzhou,Yang, Bo,Cao, Ji,Dong, Xiaowu
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p. 8621 - 8643
(2021/06/28)
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- Cycloalkyl-substituted mesyl benzamide derivatives, and preparation method and medical application thereof
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The invention relates to cycloalkyl-substitutedmesyl benzamide derivatives, and a preparation method and medical application thereof. The invention particularly discloses compounds disclosed as Formula (I) or pharmaceutically acceptable salts, stereoisomers, solvated compounds or prodrugs thereof, and a preparation method and application thereof. All the groups in the formula are defined in the specification.
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Paragraph 0122; 0123; 0124
(2017/08/25)
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- Direct synthesis of anilines and nitrosobenzenes from phenols
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A one-pot synthesis of anilines and nitrosobenzenes from phenols has been developed using an ipso-oxidative aromatic substitution (iSOAr) process. The products are obtained in good yields under mild and metal-free conditions. The leaving group effect on reactions that proceed through mixed quionone monoketals has also been investigated and a predictive model has been established.
- St Amant,Frazier,Newmeyer,Fruehauf,Read De Alaniz
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supporting information
p. 5520 - 5524
(2016/07/06)
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- Selective Aromatic C-H Hydroxylation Enabled by η6-Coordination to Iridium(III)
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We report an aromatic C-H hydroxylation protocol in which the arene is activated through η6-coordination to an iridium(III) complex. η6-Coordination of the arene increases its electrophilicity and allows for high positional selectivity of hydroxylation at the site of least electron density. Through investigation of intermediate η5-cyclohexadienyl adducts and arene exchange reactions, we evaluate incorporation of arene π-activation into a catalytic cycle for C-H functionalization.
- D'Amato, Erica M.,Neumann, Constanze N.,Ritter, Tobias
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supporting information
p. 4626 - 4631
(2015/10/06)
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- 3-3-DI-SUBSTITUTED-OXINDOLES AS INHIBITORS OF TRANSLATION INITIATION
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Compositions and methods for inhibiting translation are provided. Compositions, methods and kits for treating (1) cellular proliferative disorders, (2) non-proliferative, degenerative disorders, (3) viral infections, and/or (4) disorders associated with viral infections, using diaryloxindole compounds are described.
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Page/Page column 84-85
(2014/04/04)
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- Facile conversion of para-benzoquinones to para-alkoxyphenols with primary/secondary alcohols and amberlyst-15: A process showing novel reducing property of such alcohols
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A new efficient methodology has been developed for the synthesis of para-alkoxyphenols, an important group of anti-melanoma compounds, by heating alcoholic solutions of para-benzoquinones in the presence of amberlyst-15. The most notable feature here is the behaviour of the used primary or secondary alcohol as an effective reducing agent.
- Mondal, Rina,Guha, Chayan,Mallik, Asok K.
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supporting information
p. 86 - 89
(2014/01/06)
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- Synthesis and SAR study of novel 3,3-diphenyl-1,3-dihydroindol-2-one derivatives as potent eIF2·GTP·Met-tRNAiMet ternary complex inhibitors
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The growing recognition of inhibition of translation initiation as a new and promising paradigm for mechanism-based anti-cancer therapeutics is driving the development of potent, specific, and druggable inhibitors. The 3,3-diaryloxindoles were recently reported as potential inhibitors of the eIF2·GTP·Met-tRNAiMet ternary complex assembly and 3-{5-tert-butyl-2-hydroxyphenyl}-3-phenyl-1,3-dihydro-2H-indol-2- one #1181 was identified as the prototypic agent of this chemotype. Herein, we report our continuous effort to further develop this chemotype by exploring the structural latitude toward different polar and hydrophobic substitutions. Many of the novel compounds are more potent than the parent compound in the dual luciferase ternary complex reporter assay, activate downstream effectors of reduced ternary complex abundance, and inhibit cancer cell proliferation in the low μM range. Moreover, some of these compounds are decorated with substituents that are known to endow favorable physicochemical properties and as such are good candidates for evaluation in animal models of human cancer.
- Denoyelle, Séverine,Chen, Ting,Yang, Hongwei,Chen, Limo,Zhang, Yingzhen,Halperin, José A.,Aktas, Bertal H.,Chorev, Michael
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p. 537 - 553
(2013/10/22)
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- NOVEL ACETYL-COA CARBOXYLASE (ACC) INHIBITORS AND THEIR USE IN DIABETES, OBESITY AND METABOLIC SYNDROME
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The present invention relates to compounds of formula (I): Pharmaceutical compositions and methods that are useful in the treatment or prevention of metabolic diseases or conditions are also provided.
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Page/Page column 15
(2008/12/06)
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- NOVEL ACETYL-COA CARBOXYLASE (ACC) INHIBITORS AND THEIR USE IN DIABETES, OBESITY AND METABOLIC SYNDROME
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The present invention relates to compounds of formula (I) which inhibit acetyl-CoA carboxylase (ACC) and are useful for the prevention or treatment of metabolic syndrome, type II diabetes, obesity, atherosclerosis and cardiovascular diseases in humans.
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Page/Page column 21
(2008/06/13)
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- NOVEL ACETYL-COA CARBOXYLASE (ACC) INHIBITORS AND THEIR USE IN DIABETES, OBESITY AND METABOLIC SYNDROME
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The present invention relates to compounds of formula (I), which inhibit acetyl-CoA carboxylase (ACC) and are useful for the prevention or treatment of metabolic syndrome, type II diabetes, obesity, atherosclerosis and cardiovascular diseases in humans.
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Page/Page column 29; 36
(2008/06/13)
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- NOVEL ACETYL-COA CARBOXYLASE (ACC) INHIBITORS AND THEIR USE IN DIABETES, OBESITY AND METABOLIC SYNDROME
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The present invention relates to compounds of formula (I) which inhibit acetyl-CoA carboxylase (ACC) and are useful for the prevention or treatment of metabolic syndrome, type II diabetes, obesity, atherosclerosis and cardiovascular diseases in humans.
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Page/Page column 18
(2010/11/28)
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- N-{3-[2-(4-alkoxyphenoxy)thiazol-5-yl]-1-methylprop-2-ynyl}carboxy derivatives as acetyl-CoA carboxylase inhibitors - Improvement of cardiovascular and neurological liabilities via structural modifications
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A preliminary safety evaluation of ACC2 inhibitor 1-(S) revealed serious neurological and cardiovascular liabilities of this chemotype. A systematic structure-toxicity relationship study identified the alkyne linker as the key motif responsible for these adverse effects. Toxicogenomic studies in rats showed that 1-(R) and 1-(S) induced gene expression patterns similar to that seen with several known cardiotoxic agents such as doxorubicin. Replacement of the alkyne with alternative linker groups led to a new series of ACC inhibitors with drastically improved cardiovascular and neurological profiles.
- Gu, Yu Gui,Weitzberg, Moshe,Clark, Richard F.,Xu, Xiangdong,Li, Qun,Lubbers, Nathan L.,Yang, Yi,Beno, David W. A.,Widomski, Deborah L.,Zhang, Tianyuan,Hansen, T. Matthew,Keyes, Robert F.,Waring, Jeffrey F.,Carroll, Sherry L.,Wang, Xiaojun,Wang, Rongqi,Healan-Greenberg, Christine H.,Blomme, Eric A.,Beutel, Bruce A.,Sham, Hing L.,Camp, Heidi S.
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p. 1078 - 1082
(2008/02/04)
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- Novel acetyl-CoA carboxylase (ACC) inhibitors and their use in diabetes, obesity and metabolic syndrome
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The present invention relates to compounds of formula (I), which inhibit acetyl-CoA carboxylase (ACC) and are useful for the prevention or treatment of metabolic syndrome, type II diabetes, obesity, atherosclerosis and cardiovascular diseases in humans.
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Page/Page column 20-21
(2008/06/13)
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- Synthesis and structure-activity relationships of N-{3-[2-(4-alkoxyphenoxy) thiazol-5-yl]-1-methylprop-2-ynyl}carboxy derivatives as selective acetyl-CoA carboxylase 2 inhibitors
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A structurally novel acetyl-CoA carboxylase (ACC) inhibitor is identified from high-throughput screening. A preliminary structure-activity relationship study led to the discovery of potent dual ACC1/ACC2 and ACC2 selective inhibitors against human recombinant ACC1 and ACC2. Selective ACC2 inhibitors exhibited IC50 1000-fold selectivity against ACC1. (S)-Enantiomer 9p exhibited high ACC2 activity and lowered muscle malonyl-CoA dose-dependently in acute rodent studies, whereas (R)-enantiomer 9o was weak and had no effect on the malonyl-CoA level.
- Gu, Yu Gui,Weitzberg, Moshe,Clark, Richard F.,Xu, Xiangdong,Li, Qun,Zhang, Tianyuan,Hansen, T. Matthew,Liu, Gang,Xin, Zhili,Wang, Xiaojun,Wang, Rongqi,McNally, Teresa,Camp, Heidi,Beutel, Bruce A.,Sham, Hing L.
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p. 3770 - 3773
(2007/10/03)
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- (2R)-2-Methylchromane-2-carboxylic acids: Discovery of selective PPARα agonists as hypolipidemic agents
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A SAR study was conducted on chromane-2-carboxylic acid toward selective PPARα agonisim. As a result, highly potent, and selective PPARα agonists were discovered. The optimized compound 43 exhibited robust lowering of total cholesterol levels in hamster and dog animal models.
- Koyama, Hiroo,Boueres, Julia K.,Miller, Daniel J.,Berger, Joel P.,MacNaul, Karen L.,Wang, Pei-Ran,Ippolito, Marc C.,Wright, Samuel D.,Agrawal, Arun K.,Moller, David E.,Sahoo, Soumya P.
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p. 3347 - 3351
(2007/10/03)
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- Mesogenic Homologous Series : 4-Isopropoxyphenyl-4′-n-alkoxycinnamates and Binary Systems Comprising the Homologues of this Series
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Twelve members of the homologous series-A have been synthesised. First two members are non-mesogenic. The nematic mesophase commences as a monotropic phase from n-propoxy derivative. equation presented Series-A (where n = 1 to 16) n-Propoxy to n-heptyloxy derivatives exhibit only nematic phase. n-Octyloxy and n-decyloxy derivatives exhibit smectic and nematic phases. n-Dodecyloxy to n-hexadecyloxy derivatives exhibit only smectic phase. Seven binary systems comprised of homologues of series-A have been studied. The non-mesogens induce mesomorphism in a few binary systems. Other binary systems, where both the components are mesogens, exhibit normal behaviour of mesogenic binary systems. Results indicate that eventhough homologues of series-A contain branched alkyl chain, the binary systems do not exhibit pronounced decrease in melting behaviour.
- Vora,Vyas
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p. 507 - 511
(2007/10/03)
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- Ester composition
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The invention relates to a method for preparing an ester composition in which at least one activated phenolic ether group of a molecule is reacted with at least one haloformyl group of another molecule.
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- REACTION OF MONOSUBSTITUTED AROMATIC HYDROCARBONS WITH STYRENE
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1,1-Phenylarylethanes were obtained by the reaction of styrene with some monosubstituted aromatic hydrocarbons in the presence of titanium tetrachloride.It was established that electron-donating substituents have an effect on the yield of the arylalkylation products.
- Grushin, A. I.,Grigor'ev, V. V.,Prokof'ev, K. V.,Kozlova, N. M.
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p. 1991 - 1993
(2007/10/02)
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- SELECTIVE DEALKYLATIONS OF ARYL ALKYL ETHERS AND THIOETHERS BY SODIUM IN HMPA
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The reaction of sodium with bis- and tris(alkoxy)benzenes in HMPA gives selectively the products of monodealkylation.The reaction proceeds through a dianion which fragments into an alkyl and an aryloxy anion.The positional selectivity of this fragmentation is governed by the structure of both the alkyl and aryloxy groups.With bis- and tris(alkoxy)benzenes which for symmetry reasons can afford aryloxy anions having the same basicity, the dealkylation involves exlusively the less substituted alkyl group.On the contrary, in the asymmetric terms, the positional selectivity of the dealkylation process is governed by the basicity of the aryloxy anion.On the basis of these concepts several efficient and synthetically useful reactions have been developed.In most cases the selectivity obtained in the present reactions in different from that observed with other previously developed methods which use sodium methoxide or sodium alkenethiolates in HMPA.It is shown that the appropriate choice of the reagent allows selective dealkylation of the desired alkoxy group of a poly(alkoxy)benzene.The reaction of sodium with bis(alkylthio)benzenes in HMPA gives the bis(mercapto)benzenes.If the reduction is carried out with a solution of sodium in HMPA, the reaction gives instead the products of monodealkylation.This however is not selective.It is suggested that in the case of thioethers the dealkylation products originate from the fragmentation of the radical anions.
- Testaferri, L.,Tiecco, M.,Tingoli, M.,Chianelli, D.,Montanucci, M.
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p. 3687 - 3692
(2007/10/02)
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