- FLUORESCENT PROBES FOR DRUG PERMEABILITY IN GRAM NEGATIVE BACTERIA
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Described are compounds and methods useful in measuring membrane permeability and efflux transporter activity in bacteria, including multidrug resistance Gram negative bacteria.
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- 5 - Fluoro - 2, 4 - disubstituted amino pyrimidine derivative and its preparation and use
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The invention belongs to the field of chemical medicine and particularly relates to a 5-fluorine-2,4-bis-substituted aminopyrimidine derivative and a preparation method and application thereof. The structure of the 5-fluorine-2,4-bis-substituted aminopyri
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- Design, synthesis and anti leukemia cells proliferation activities of pyrimidylaminoquinoline derivatives as DOT1L inhibitors
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A series of novel pyrimidylaminoquinoline derivatives 8(a-i) and 9(a-i) containing amino side chain, and the bisaminoquinoline analogs 3(b-e) have been designed and synthesized by structural modifications on a lead DOT1L inhibitor, 3a. All the compounds have been evaluated for their DOT1L inhibitory activities. The results showed that most of the compounds have strong anti DOT1L activities. Compounds 3e, 8h and 9e are the most potential ones from each category with the IC50 values of 1.06 ± 0.35 μM, 5.72 ± 1.56 μM and 3.55 ± 1.28 μM, respectively. Such inhibitors expressed significant binding interactions with DOT1L by surface plasmon resonance (SPR)-based binding assay. The results of molecular docking experiments suggested that they could occupy the SAM binding pocket of DOT1L. Compounds 8h and 9e exhibited better inhibitory activities but poor selectivities against the both MLL-rearranged MV4-11 cells and the non MLL-rearranged Kasumi-1 cells than those of 3a and 3e, which suggested that the introduction of the amino side chain would be beneficial for their anti leukemia cells proliferation activities, possibly due to the improvement of the fat solubility. Additionally, the direct cellular inhibition activities were found that compound 9e could effectively down-regulate both the level of H3k79 methylation and MLL-rearranged leukemia gene expression of Hoxa9 and Meis1 in MV4-11 in the qRT-PCR and western blot studies. These observations suggested DOT1L was one of the potential targets but perhaps not the most pivotal one for these compounds, which made their poor selectivities against leukemia cells proliferation.
- Zhang, Li,Chen, Yantao,Liu, Na,Li, Linjuan,Xiao, Senhao,Li, Xiaoliu,Chen, Kaixian,Luo, Cheng,Chen, Shijie,Chen, Hua
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p. 649 - 654
(2018/07/31)
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- A method for inhibiting PRMT7 compound and its preparation method and application (by machine translation)
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The invention belongs to the field of chemical medicine, and in particular relates to a method for inhibiting PRMT7 compound, its formula is as follows: In some embodiments of the compounds proved that, this compound can to PRMT7 produce better inhibitio
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- Small molecule antagonists of cell-surface heparan sulfate and heparin-protein interactions
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Surfen, bis-2-methyl-4-amino-quinolyl-6-carbamide, was previously reported as a small molecule antagonist of heparan sulfate (HS), a key cell-surface glycosaminoglycan found on all mammalian cells. To generate structure-activity relationships, a series of rationally designed surfen analogs was synthesized, where its dimeric structure, exocyclic amines, and urea linker region were modified to probe the role of each moiety in recognizing HS. An in vitro assay monitoring inhibition of fibroblast growth factor 2 binding to wild-type CHO cells was utilized to quantify interactions with cell surface HS. The dimeric molecular structure of surfen and its aminoquinoline ring systems was essential for its interaction with HS, and certain dimeric analogs displayed higher inhibitory potency than surfen and were also shown to block downstream FGF signaling in mouse embryonic fibroblast cells. These molecules were also able to antagonize other HS-protein interactions including the binding of soluble RAGE to HS. Importantly, selected molecules were shown to neutralize heparin and other heparinoids, including the synthetic pentasaccharide fondaparinux, in a factor Xa chromogenic assay and in vivo in mice. These results suggest that small molecule antagonists of heparan sulfate and heparin can be of therapeutic potential for the treatment of disorders involving glycosaminoglycan-protein interactions.
- Weiss, Ryan J.,Gordts, Philip L. S. M.,Le, Dzung,Xu, Ding,Esko, Jeffrey D.,Tor, Yitzhak
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p. 5984 - 5993
(2015/09/28)
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- Synthesis and antibacterial activities of some substituted quinolines
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p-Anisidine (1) on treatment with ethyl acetoacetate in refluxing ethanol for 4 h gave ethyl-3-[(4-methoxyphenyl)imino]butanoate (2) which on thermal cyclization in hot Dowtherm oil at 250 °C gave 4-hydroxy-6-methoxy-2-methylquinoline (3). The latter on h
- Anukumari,Rao, M. Anand,Dubey
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p. 2947 - 2950
(2015/12/12)
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- GTPase inhibitors and methods of use and crystal structure of RAC-1 GTPase
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The preferred embodiments generally relate to methods and compositions that affect the GTP-binding activity of members of the Rho family GTPases, preferably Rac (Rac1, Rac2 and/or Rac3), such compositions include compounds that modulate the GTP/GDP exchan
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Page/Page column 28
(2008/06/13)
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- 4-Aminoquinoline melanin-concentrating hormone 1-receptor (MCH1R) antagonists
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Structure-activity relationships of a 4-aminoquinoline MCH1R antagonist lead series were explored by synthesis of analogs with modifications at the 2-, 4-, and 6-positions of the original HTS hit. Improvements to the original screening lead included lipophilic groups at the 2-position and biphenyl, cyclohexyl phenyl, and hydrocinnamyl carboxamides at the 6-position. Modifications of the 4-amino group were not well tolerated.
- Jiang, Jinlong,Lin, Peter,Hoang, Myle,Chang, Lehua,Tan, Carina,Feighner, Scott,Palyha, Oksana C.,Hreniuk, Donna L.,Pan, Jie,Sailer, Andreas W.,Morin, Nancy R.,MacNeil, Douglas J.,Howard, Andrew D.,Van der Ploeg, Lex H.T.,Goulet, Mark T.,DeVita, Robert J.
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p. 5275 - 5279
(2007/10/03)
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- GTPASE INHIBITORS AND USE THEREOF FOR CONTROLLING PLATELET HYPERACTIVITY
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The preferred embodiments generally relate to methods and compositions that affect the GTP-binding activity of members of the Rho family GTPases, preferably Rac (Rac1, Rac2 and/or Rac3), such compositions include compounds that modulate the GTP/GDP exchan
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Page/Page column 42-43
(2008/06/13)
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- GTPASE INHIBITORS AND METHODS OF USE
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The preferred embodiments generally relate to methods and compositions that affect the GTP-binding activity of members of the Rho family GTPases, preferably Rac (Rac1, Rac2 and/or Rac3), such compositions include compounds that modulate the GTP/GDP exchan
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Page/Page column 46-45
(2008/06/13)
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- A new synthetic approach of N-(4-amino-2-methylquinolin-6-yl)-2-(4- ethylphenoxymethyl)benzamide (JTC-801) and its analogues and their pharmacological evaluation as nociceptin receptor (NOP) antagonists
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A series of 4-amino-2-methylquinoline and 4-aminoquinazoline derivatives, including the reference NOP antagonist JTC-801, were synthesized by an alternative pathway and their in vitro pharmacological properties were investigated. 3-Substitution of the qui
- Sestili, Isabella,Borioni, Anna,Mustazza, Carlo,Rodomonte, Andrea,Turchetto, Luciana,Sbraccia, Maria,Riitano, Daniela,Del Giudice, Maria Rosaria
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p. 1047 - 1057
(2007/10/03)
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- Amide derivatives and nociceptin antagonists
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The present invention relates to a compound of the formula [1′] wherein R2is lower alkyl optionally substituted by hydroxy, amino and the like, ring B is phenyl, thienyl and the like, E is a single bond, —O—, —S— and the like, ring G is aryl, heterocyclic group and the like, R5is halogen atom, hydroxy, lower alkyl optionally substituted by halogen atom etc., and the like, t is 0 or an integer of 1 to 5, when t is an integer of 2 to 5, each R5may be the same or different, m is 0 or an integer of 1 to 8, and n is 0 or an integer of 1 to 4, and a nociceptin antagonist containing compound [1′] as an active ingredient. The compound [1′] shows, due to nociceptin antagonistic action, analgesic effect against sharp pain such as postoperative pain and the like. The present invention also relates to the use of certain amide derivative inclusive of compound [1′] as a nociceptin antagonist or analgesic.
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- 4-Aminoquinolines: Novel nociceptin antagonists with analgesic activity
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Small-molecule nociceptin antagonists were synthesized to examine their therapeutic potential. After a 4-aminoquinoline derivative was found to bind with the human ORL1 receptor, a series of 4-aminoquinolines and related compounds were synthesized and their binding was evaluated. Elucidation of structure - Activity relationships eventually led to the optimum compounds. One of these compounds, N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl)benzamide hydrochloride (11) not only antagonized nociceptin-induced allodynia in mice but also showed analgesic effect in a hot plate test using mice and in a formalin test using rats. Its analgesic effect was not antagonized by the opioid antagonist naloxone. These results indicate that this nociceptin antagonist has the potential to become a novel type of analgesic that differs from μ-opioid agonists.
- Shinkai,Ito,Iida,Kitao,Yamada,Uchida
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p. 4667 - 4677
(2007/10/03)
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- Substituted aminoquinolines as modulators of chemokine receptor activity
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The present invention is directed to aminoquinolines of Formula I: STR1 (wherein R 1, R 2, R 3, and R 4 are defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, and/or CXCR-4.
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- Substituted 4,6-Diaminoquinolines as Inhibitors of C5a Receptor Binding
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The anaphylatoxin C5a is implicated in a number of inflammatory diseases.It is a highly cationic protein with 13 of 74 amino acids being either arginine or lysine.A search focusing on positively charged molecules, particularly amine-containing functionali
- Lanza, Thomas J.,Durette, Philippe L.,Rollins, Thomas,Siciliano, Salvatore,Cianciarulo, Dana N.,et al.
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p. 252 - 258
(2007/10/02)
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