- Asymmetric Total Synthesis and Evaluation of Antitumor Activity of Ophiorrhisine A and Its Derivatives
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The first asymmetric total synthesis of ophiorrhisine A (1), a new cyclic tetrapeptide isolated from Ophiorrhiza nutans, was accomplished via an intramolecular aromatic nucleophilic substitution reaction (IMSNAr) of a linear tripeptide to construct a 14-membered paracyclophane ring, resulting in confirmation of its structure and absolute configuration. The structure-activity relationship study of 1 and its derivatives demonstrated that some derivatives possessed cytotoxicity toward human cancer cell lines A549, HT29, and HCT116.
- Onozawa, Tadayoshi,Kitajima, Mariko,Kogure, Noriyuki,Takayama, Hiromitsu
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p. 15312 - 15322
(2019/01/03)
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- p27 PROTEIN INDUCER
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The present invention provides a p27 protein inducing agent comprising a compound represented by general formula (11) below or pharmaceutically acceptable salt thereof as an active ingredient: wherein G 1 , G 2 , G 3 and G 8 are each independently selected from -N= etc., Ring G 6 is selected from divalent aryl etc., A is selected from amino etc., G 4 is selected from oxygen etc., G 5 is selected from oxygen etc., G 7 is selected from -CH 2 - etc., and R 2 is selected from C 1-6 alkyl etc.
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Paragraph 2917-2921
(2016/10/08)
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- 4-([1,2,4]Triazolo[1,5-a]pyridin-6-yl)-5(3)-(6-methylpyridin-2-yl)imidazole and -pyrazole derivatives as potent and selective inhibitors of transforming growth factor-β type i receptor kinase
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A series of 4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5(3)-(6-methylpyridin-2- yl)imidazoles and -pyrazoles 14a-c, 15a-c, 16a, 16b, 19a-d, 21a, and 21b has been synthesized and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. Among them, the pyrazole derivative 21b inhibited ALK5 phosphorylation with an IC50 value of 0.018 μM and showed 95% inhibition at 0.03 μM in a luciferase reporter assay using HaCaT cells permanently transfected with p3TP-luc reporter construct. The 21b showed a high selectivity index of 284 against p38α MAP kinase. The binding pose of 21b generated by docking analysis reveals that it fits well into the ATP binding cavity of ALK5 by forming several hydrogen bond interactions.
- Jin, Cheng Hua,Krishnaiah, Maddeboina,Sreenu, Domalapally,Subrahmanyam, Vura Bala,Park, Hyun-Ju,Park, So-Jung,Sheen, Yhun Yhong,Kim, Dae-Kee
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supporting information
p. 2724 - 2732
(2014/05/06)
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- Discovery of N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin- 2-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline (EW-7197): A highly potent, selective, and orally bioavailable inhibitor of TGF-β type I receptor kinase as cancer immunotherapeutic/antifibrotic agent
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A series of 2-substituted-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6- methylpyridin-2-yl)imidazoles was synthesized and evaluated to optimize a prototype inhibitor of TGF-β type I receptor kinase (ALK5), 6. Combination of replacement of a quinoxalin-6-yl moiety of 6 with a [1,2,4]triazolo[1,5-a] pyridin-6-yl moiety, insertion of a methyleneamino linker, and a o-F substituent in the phenyl ring markedly increased ALK5 inhibitory activity, kinase selectivity, and oral bioavailability. The 12b (EW-7197) inhibited ALK5 with IC50 value of 0.013 μM in a kinase assay and with IC50 values of 0.0165 and 0.0121 μM in HaCaT (3TP-luc) stable cells and 4T1 (3TP-luc) stable cells, respectively, in a luciferase assay. Selectivity profiling of 12b using a panel of 320 protein kinases revealed that it is a highly selective ALK5/ALK4 inhibitor. Pharmacokinetic study with 12b·HCl in rats showed an oral bioavailability of 51% with high systemic exposure (AUC) of 1426 ng × h/mL and maximum plasma concentration (Cmax) of 1620 ng/mL. Rational optimization of 6 has led to the identification of a highly potent, selective, and orally bioavailable ALK5 inhibitor 12b.
- Jin, Cheng Hua,Krishnaiah, Maddeboina,Sreenu, Domalapally,Subrahmanyam, Vura B.,Rao, Kota S.,Lee, Hwa Jeong,Park, So-Jung,Park, Hyun-Ju,Lee, Kiho,Sheen, Yhun Yhong,Kim, Dae-Kee
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supporting information
p. 4213 - 4238
(2014/06/09)
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- NOVEL COMPOUNDS FOR MODULATION OF ROR-GAMMA ACTIVITY
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The present invention relates to aryl sulfones and related compounds that are modulators of ROR-gamma receptors. The invention also provides pharmaceutical compositions comprising these modulators, and methods of modulating ROR-gamma receptors using them. Also provided are methods of using aryl sulfones and related compounds as modulators of ROR-gamma to treat ROR-gamma mediated diseases
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Paragraph 00574
(2014/03/22)
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- COUMARIN DERIVATIVE, PHARMACEUTICAL COMPOSITION AND USE THEREOF
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The present invention relates to a coumarin derivative of formula (I): wherein X, Y1, Y2, Y3, R1, R2, R3 and R4 are as defined herein, or a pharmaceutically acceptable salt or so
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Page/Page column 23
(2013/02/28)
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- Discovery of a clinical stage multi-kinase inhibitor sodium (E)-2-{2-methoxy-5-[(2′,4′,6′-trimethoxystyrylsulfonyl)methyl] phenylamino}acetate (ON 01910.Na): Synthesis, structure-activity relationship, and biological activity
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Cyclin D proteins are elevated in many cancer cells, and targeted deletion of cyclin D1 gene in the mammary tissues protects mice from breast cancer. Accordingly, there is an increasing awareness of this novel nonenzymatic target for cancer therapeutics. We have developed novel, nonalkylating styrylbenzylsulfones that induce cell death in wide variety of cancer cells without affecting the proliferation and survival of normal cells. The development of derivatized styrylbenzylsulfones followed logically from a tumor cell cytotoxicity screen performed in our laboratory that did not have an a priori target profile. Modifications of some of the precursor molecules led to lead optimization with regard to tumor cell cytotoxicity. In this report we describe the synthesis and structure-activity relationships of novel, nonalkylating (E)-styrylbenzylsulfones and the development of the novel anticancer agent sodium (E)-2-{2-methoxy-5-[(2′,4′,6′- trimethoxystyrylsulfonyl)methyl]phenylamino}acetate (ON 01910.Na), which is in phase III trials for myelodysplastic syndromes (MDS) associated with aberrant expression of cyclin D proteins.
- Reddy, M. V. Ramana,Venkatapuram, Padmavathi,Mallireddigari, Muralidhar R.,Pallela, Venkat R.,Cosenza, Stephen C.,Robell, Kimberly A.,Akula, Balaiah,Hoffman, Benjamin S.,Reddy, E. Premkumar
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experimental part
p. 6254 - 6276
(2011/11/01)
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- Efficient and diversity-oriented total synthesis of Riccardin C and application to develop novel macrolactam derivatives
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Riccardin C (RC, 1) is a macrocyclic bis(bibenzyl) natural product exhibiting remarkable biological activity as a nuclear liver X receptors (LXRs) ligand and a lipid metabolism mediator. RC is expected to be a lead compound to develop drugs for atherosclerotic diseases, and therefore exploiting diversity-oriented synthesis of RC is a promising approach to drug discovery. In this paper, we report novel total synthesis of RC (7.4% overall yield in 16 steps) by using the intramolecular SNAr reaction as key cyclization reaction. This is the first example of efficient macrocyclization using 3-nitro-4-fluorostilbene as an electrophile. The methodology could be applied to synthesize novel lactam analogs of RC. The diversity-oriented synthesis of RC is versatile method for the synthesis of various types of bis(bibenzyl) natural products and their derivatization.
- Iwashita, Masazumi,Fujii, Shinya,Ito, Shigeru,Hirano, Tomoya,Kagechika, Hiroyuki
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experimental part
p. 6073 - 6082
(2011/08/22)
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- Total synthesis of plagiochin D by an intramolecular SNAr reaction
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The total synthesis of plagiochin D, a macrocyclic bis(bibenzyl) compound isolated from the liverwort plagiochila acanthophylla, has been accomplished. Closure of the key 16-membered ring, which contained biphenyl ether and biaryl units, was achieved in good yield by an intramolecular SNAr reaction. The Suzuki and Wittig protocols proved to be powerful tools for the construction of a linear precursor that was crucial for ring cyclization. Copyright
- Cortes Morales, Julio Cesar,Guillen Torres, Alejandro,Gonzalez-Zamora, Eduardo
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scheme or table
p. 3165 - 3170
(2011/06/28)
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- NOVEL COUMARIN DERIVATIVE HAVING ANTITUMOR ACTIVITY
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The present invention provides a compound represented by general formula (1) below or a pharmaceutically acceptable salt thereof: wherein: X is selected from heteroaryl etc., Y1 and Y2 are selected from -N= etc., Y3 and Y4 are selected from -CH= etc., A is selected from sulfamide etc., R1 is selected from hydrogen etc., and R2 is selected from C1-6 alkyl etc. The compound or salt has sufficiently high antitumor activity, and is useful in the treatment of cell proliferative disorders, particularly cancers. The present invention also provides a pharmaceutical composition containing the compound or salt as an active ingredient.
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Page/Page column 199
(2008/12/04)
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- Benzylbenzimidazolyl derivatives
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Novel benzyl-benzimidazolyl derivatives as inhibitors of tyrosine kinases, particularly TIE-2, VEGFR, PDGFR, FGFR and/or FLT/KDR, for the treatment of tumors, according to formula (I), wherein the radicals R1, R2, r and s are defined according to Claim (1).
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- BENZYL-BENZIMIDAZOLYL DERIVATIVES
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Novel benzyl-benzimidazolyl derivatives as inhibitors of tyrosine kinases, particularly TIE-2, VEGFR, PDGFR, FGFR and/or FLT/KDR, for the treatment of tumors, according to formula (I), wherein the radicals R1, R2, r and s are defined according to Claim (1).
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Page/Page column 53
(2010/02/11)
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- Solid phase synthesis of vancomycin mimics
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A solid phase synthesis of a model system of the DE ring system of vancomycin is described. The synthesis involved biocatalytic resolutions of unnatural amino acids, is compatible with conventional solid phase peptide synthesis and contains as the key step: an on-be.ad SNAr cyclization. Binding of a cyclic peptide to the carboxylate of N-Ac-D-Ala was demonstrated. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.
- Arnusch, Christopher J.,Pieters, Roland J.
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p. 3131 - 3138
(2007/10/03)
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- A rapid access to biaryl ether containing macrocycles by pairwise use of Ugi 4CR and intramolecular S(N)Ar-based cycloetherification.
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[reaction: see text] From readily accessible starting materials, macrocycles with an endo aryl-aryl ether bond are synthesized in only two operations by combination of the Ugi four-component reaction and an intramolecular S(N)Ar reaction. The nitro group serves as an activator for the macrocyclization and provides a handle for the introduction of functional group diversity. A Ugi reaction promoted by ammonium chloride in aprotic solvent is documented for the first time.
- Cristau,Vors,Zhu
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p. 4079 - 4082
(2007/10/03)
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- Synthetic studies towards the synthesis of western and eastern chloropeptin I, II subunits
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The western subunit (16-membered ring) was synthesized by the intramolecular SNAr reaction while the first 16-membered ring compound was obtained as a model of the eastern subunit via an intramolecular Ni0 mediated coupling reaction.
- Roussi, Georges,Gonzalez Zamora, Eduardo,Carbonnelle, Annie-Claude,Beugelmans, Rene
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p. 2041 - 2063
(2007/10/03)
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- Synthetic studies towards glycopeptide antibiotics: Synthesis of the 16-membered cyclic tripeptide (DOEG ring) system of teicoplanin
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The synthesis of the 16-membered cyclic DOEG ring system of teicoplanin, which forms the binding pocked for the carboxylate region of terminal D-Ala-D-Ala of the bacterial cell wall via macroetherification of linear tripeptide 20 is described.
- Rama Rao,Laxma Reddy,Srinivasa Rao,Vittal,Reddy,Pathi
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p. 3023 - 3026
(2007/10/03)
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- SNAr-Based Macrocyclization: An Application to the Synthesis of Vancomycin Family Models
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The first examples of macrocyclization using the intramolecular SNAr reaction are reported.The method has allowed the efficient preparation of the elusive 16-membered macrocyclic COD and DOE rings related to vancomycin.The mild conditions used allow the incorporation of very racemization-prone amino acids, such as p-methoxyphenylglycine, into the peptide chain.After serving as an activator, the nitro group ortho to the diaryl ether linkage is converted either into a chlorine or a hydrogen atom, thus achieving the substitution pattern found in the vancomycin family of glycopeptides.When compound 20 was submitted to the same macrocyclization conditions, two atropisomers 21 and 22 were isolated and characterized.
- Beugelmans, Rene,Singh, Girij Pal,Bois-Choussy, Michele,Chastanet, Jacqueline,Zhu, Jieping
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p. 5535 - 5542
(2007/10/02)
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- The first examples of S(N)Ar-based macrocyclisation: Synthesis of model carboxylate-binding pockets of vancomycin
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Model carboxylate-binding pocket C-O-D rings of vancomycin and related glycopeptides were efficiently synthesized by intramolecular S(N)Ar reaction.
- Beugelmans,Zhu,Husson,Bois-Choussy,Singh
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p. 439 - 440
(2007/10/02)
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