- Discovery of AL-GDa62 as a Potential Synthetic Lethal Lead for the Treatment of Gastric Cancer
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Diffuse gastric cancer and lobular breast cancer are aggressive malignancies that are frequently associated with inactivating mutations in the tumor suppressor gene CDH1. Synthetic lethal (SL) vulnerabilities arising from CDH1 dysfunction represent attrac
- Beetham, Henry,Bougen-Zhukov, Nicola,Cameron, Scott A.,Evans, Gary B.,Fraser, Michael G.,Guilford, Parry J.,Harris, Lawrence D.,Luxenburger, Andreas,Schmidt, Dorian
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p. 18114 - 18142
(2021/12/17)
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- Synthesis and evaluation of azalamellarin N and its A-ring-modified analogues as non-covalent inhibitors of the EGFR T790M/L858R mutant
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Azalamellarin N, a synthetic lactam congener of the marine natural product lamellarin N, and its A-ring-modified analogues were synthesized and evaluated as potent and non-covalent inhibitors of the drug-resistant epidermal growth factor receptor T790M/L8
- Fukuda, Tsutomu,Anzai, Mizuho,Nakahara, Akane,Yamashita, Kentaro,Matsukura, Kazuaki,Ishibashi, Fumito,Oku, Yusuke,Nishiya, Naoyuki,Uehara, Yoshimasa,Iwao, Masatomo
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- COMPLEMENT MODULATORS AND RELATED METHODS
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The present disclosure presents compounds and compositions that interact with complement components. Some compounds inhibit complement activity. Included are small molecule compounds and compositions that function as C5 inhibitor compounds. Methods for inhibiting complement activity and methods of treating complement-related indications with the C5 inhibitor compounds and compositions are provided.
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Paragraph 0759
(2020/10/20)
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- Discovery of 1,6-naphthyridinone-based MET kinase inhibitor bearing quinoline moiety as promising antitumor drug candidate
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A series of 1,6-naphthyridinone-based MET kinase inhibitors bearing quinoline moiety in block A were designed and synthesized based on the structures of Cabozantinib and our reported compound IV. Extensive SAR and DMPK studies led to the identification of 20j, a potent and orally bioavailable MET kinase inhibitor with favorable kinase selectivity. More importantly, 20j exhibited statistically significant tumor growth inhibition (Tumor growth inhibition/TGI of 131%, 4/6 partial regression/PR) in the U-87 MG xeograft model, which is superior to that of Cabozantinib (TGI of 97%, 2/6 PR), and significantly better than that of compound IV (TGI of 15%, 0/6 PR) at the same dose (12.5 mg/kg). Combined with favorable in vitro potency, kinase selectivity, pharmacokinetic profile and in vivo efficacy, the promising antitumor drug candidate 20j has subsequently advanced into preclinical research.
- Chen, Tao,Fang, Wei-Rong,Huang, Wei,Li, Yun-Man,Liu, Peng-Fei,Zhuo, Lin-Sheng
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- Naphthyridine compound and pharmaceutical composition as well as applications thereof
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The invention relates to the field of biological medicines and discloses a naphthyridine compound and a pharmaceutical composition as well as applications thereof. The naphthyridine compound has a structure shown in a formula (I) or a stereisomer, a geometric isomer, a tautomer, nitric oxide, hydrate, solvate, metabolite, a pharmaceutically acceptable salt or a prodrug. The naphthyridine compound disclosed by the invention has an anti-tumor effect which is obviously superior to the anti-tumor effect of the prior art. And moreover, the naphthyridine compound disclosed by the invention can treat diseases mediated by protein kinase.
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- Preparation method of 7-benzyloxy-6-methoxy-4-hydroxyquinoline
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The invention discloses a preparation method of 7-benzyloxy-6-methoxy-4-hydroxyquinoline. The method comprises the following steps: under the action of anhydrous p-methylbenzenesulfonic acid, carrying out condensation reaction on 3-benzyloxy-4-methoxyanil
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- Aryloxy quinoline derivatives and their use in therapy
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Disclosed herein are aryloxy quinolines derivatives,and the said compounds are compounds of formula (I) or pharmaceutically acceptable salts thereof or solvates, wherein R1, R2, R3, R4, m, n, X, Z, Ar are defined detailedly in the description. Furthermore, medicaments comprising said compounds or salts as active components and the use for treating conditions and disorders relating to protein-tyrosine kinase receptors, especially c-Met, VEGFR are also described.
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- Synthesis and anticancer activity of 4-aza-daurinol derivatives
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Daurinol, a natural aryl naphthalene lactone, has been reported to have antiproliferative activity against various cell lines, and has also been shown to be efficacious in an in vivo xenograft mouse model. In this study, we tried to discover a new scaffold that enables both rapid structure-activity relationship study of daurinol and scalable synthesis of active compounds. 4-Aza-daurinol, a bioisosterism-based scaffold of daurinol, was designed and 17 analogues were synthesized and evaluated against five representative cancer cell lines. Among them, the 2,3-dihydrobenzo[b][1,4]dioxinyl derivative was found to be the most potent and showed similar activity and tendency as daurinol.
- Hayat, Faisal,Park, Seung-Hyuk,Choi, Nam-Song,Lee, Juyeun,Park, Sung Jean,Shin, Dongyun
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p. 1975 - 1982
(2015/11/24)
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- Identification of 3-amido-4-anilinoquinolines as potent and selective inhibitors of CSF-1R kinase
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3-Amido-4-anilinoquinolines are potent and highly selective inhibitors of CSF-1R. Their synthesis and SAR is reported, along with initial efforts to optimize the physical properties and PK through modifications at the quinoline 6- and 7-positions.
- Scott, David A.,Balliet, Carrie L.,Cook, Donald J.,Davies, Audrey M.,Gero, Thomas W.,Omer, Charles A.,Poondru, Srinivasu,Theoclitou, Maria-Elena,Tyurin, Boris,Zinda, Michael J.
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scheme or table
p. 697 - 700
(2009/08/15)
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- QUINOLINE AND QUINOXALINE DERIVATIVES AS INHIBITORS OF KINASE ENZYMATIC ACTIVITY
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Compounds of formula (IA) or (IB), are inhibitors of aurora kinase activity: Formula (IA), (IB) wherein -L1Y1-[CH2]z- is a linker radical wherein Y1, L1 and z are as defined in the claims; R6 is C1-C4alkoxy, hydrogen or halo; W represents a bond, -CH2-, -O-, -S-, -S(=O)2-, or -NR5- where R5 is hydrogen or C1-C4 alkyl; Q is =N-, =CH- or =C(X1)- wherein X1 is cyano, cyclopropyl or halo; linker radicals L2 are as defined in the claims; R is a radical of formula (X) or (Y): wherein R1 is a carboxylic acid group (-COOH), or an ester group which is hydrolysable by one or more intracellular carboxylesterase enzymes to a carboxylic acid group; R4 is hydrogen; or optionally substituted C1-C6 alkyl, C3-C7 cycloalkyl, aryl, aryl(C1-C6 alkyl)-, heteroaryl, heteroaryl(C1-C6 alkyl)-, -(C=O)R3, -(C=O)OR3, or -(C=O)NR3 wherein R3 is hydrogen or optionally substituted (C1-C6)alkyl, C3-C7 cycloalkyl, aryl, aryl(C1-C6 alkyl)-, heteroaryl, or heteroaryl(C1-C6 alkyl)-; R41 is hydrogen or optionally substituted C1-C6 alkyl; and D is a monocyclic heterocyclic ring of 5 or 6 ring atoms.
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- SUBSTITUTED N-ARYL BENZAMIDES AND RELATED COMPOUNDS FOR TREATMENT OF AMYLOID DISEASES AND SYNUCLEINOPATHIES
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Substituted diaryl compounds of the Formulae (I, II, III), where the variables are as defined in the claims, and their pharmaceutically acceptable derivatives, their synthesis, pharmaceutical compositions containing them, and their use in the treatment of amyloid diseases, including A? amyloidosis, such as observed in Alzheimer's disease, IAPP amyloidosis, such as observed in type 2 diabetes, and synucleinopathies, such as observed in Parkinson's disease, and the manufacture of medicaments for such treatment are provided.
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Page/Page column 92
(2008/06/13)
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- A series of bisaryl imidazolidin-2-ones has shown to be selective and orally active 5-HT2C receptor antagonists
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Bisaryl cyclic ureas have been identified as high affinity 5-HT 2C receptor antagonists with selectivity over 5-HT2A and 5-HT2B. Compounds such as 8 and 22 have shown oral activity in a centrally mediated pharmacodynamic model of 5-HT2C function in rodents.
- Goodacre, Caroline J.,Bromidge, Steven M.,Clapham, David,King, Frank D.,Lovell, Peter J.,Allen, Mike,Campbell, Lorraine P.,Holland, Vicky,Riley, Graham J.,Starr, Kathryn R.,Trail, Brenda K.,Wood, Martyn D.
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p. 4989 - 4993
(2007/10/03)
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- Antimitotic and cell growth inhibitory properties of combretastatin A-4-like ethers
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A series of diarylamines, diaryl and arylbenzyl ethers based on combretastatin A-4 was prepared and evaluated for anticancer activity. 2-Methoxy-5-(3',4',5'-trimethoxyphenoxymethyl)phenol was the most active (IC50, K562 20 nM) and caused significant G2/M cell cycle arrest. (C) 2000 Elsevier Science Ltd.
- Lawrence, Nicholas J.,Rennison, David,Woo, Meiki,McGown, Alan T.,Hadfield, John A.
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- Quinazolines: Combined type 3 and 4 phosphodiesterase inhibitors
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A series of quinazolines has been prepared and evaluated for its ability to inhibit cyclic AMP phosphodiesterase type 3, type 4A, 4B and 4D. The most potent inhibitors showed IC50 values in the nanomolar range for type 3 and type 4 isoforms and bind with high affinity to the [3H]rolipram binding site. These quinazolines represent a new family of potent mixed PDE 3 / 4 inhibitors and are expected to have a therapeutic potential.
- Charpiot, Brigitte,Brun, Jvan,Donze, Irene,Naef, Reto,Stefani, Monique,Mueller, Thomas
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p. 2891 - 2896
(2007/10/03)
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- Lewis acid-controlled regioselectivity in reactions of styrenyl systems with benzoquinone monoimides: New regioselective syntheses of substituted 2-aryl-2,3-dihydrobenzofurans, 2-aryl-2,3-dihydroindoles, and 2-arylindoles
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Reactions of 4-(N-phenylsulfonyl)-2-alkoxy-1,4-benzoquinone monoimines 2-4 with electron-rich propenylbenzenes promoted by BF3 yield 7-alkoxy-2-aryl-3-methyl-5-[(N-phenylsulfonyl)amino]-2,3-dihydrobenzofurans 5-7 nearly exclusively, whereas promotion of the reactions by Ti4+ gives mixtures of the dihydrobenzofurans and their N-(phenylsulfonyl)-6-alkoxy-2-aryl-5-hydroxy-3-methyl-2,3-dihydroindole isomers 8-10, depending upon substituents present on the propenylbenzene. However, reactions promoted with excess Ti4+, as mixtures of TiCl4:Ti(OiPr)4, give the dihydroindoles as nearly the exclusive products. Evidence for a mechanism involving initial 5 + 2 cycloaddition of the Lewis acid-bound quinone monoimide with the propenylbenzene is found in reactions of styrenes 1f/g with monoimide 3 in which 7-aryl-3-hydroxy-6-methylbicyclo[3.2.1]oct-3-ene-2,8-diones 33 (5 + 2 adducts) are isolated. These reactions have been applied to stereoselective syntheses of pterocarpans bearing N-phenylsulfonyl groups, azapterocarpans and diazapterocarpans. In addition, DDQ oxidation of derivatives of several of the 2-aryl-2,3-dihydroindoles afford the corresponding 2-arylindoles in good yield. Finally, the experimental details of a general synthetic approach to 7-alkoxy-benzofuranoid neolignans, including (±)-licarin B and eupomatenoids-1 and -12 are reported.
- Engler, Thomas A.,Chai, Wenying,LaTessa, Kenneth O.
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p. 9297 - 9308
(2007/10/03)
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- Cycloaddition reactions of 1,4-benzoquinone mono- And bisimides with styrenyl systems: New syntheses of nitrogen substituted azapterocarpans, pterocarpans, 2-aryl-2,3-dihydroindoles and -dihydrobenzofurans
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Lewis acid-promoted reactions of 1,4-benzoquinones and 1,4-benzoquinone bis- and monoimides with various 2H-chromenes, N-tosyl-1,2-dihydroquinolines and styrenes regio- and stereoselectively produce the title compounds in good yields.
- Engler, Thomas A.
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p. 2713 - 2716
(2007/10/02)
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- Rearrangement of a Pyranone to a Benzothiazole
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The conversion of 2-chloromethyl-5-methoxy-4H-pyran-4-one to 2-amino-5-hydroxy-6-methoxybenzothiazole hydrochloride under mild reaction conditions has been observed.The synthesis of the identical benzothiazole by an alternate unequivocal method is also reported.
- White, R.L.,Schwan, Thomas J.,Alaimo, R.J.
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p. 817 - 818
(2007/10/02)
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