- Discovery of novel small-molecule inhibitors of BRD4 using structure-based virtual screening
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Bromodomains (BRDs) are epigenetic readers that recognize acetylated-lysine (KAc) on proteins and are implicated in a number of diseases. We describe a virtual screening approach to identify BRD inhibitors. Key elements of this approach are the extensive design and use of substructure queries to compile a set of commercially available compounds featuring novel putative KAc mimetics and docking this set for final compound selection. We describe the validation of this approach by applying it to the first BRD of BRD4. The selection and testing of 143 compounds lead to the discovery of six novel hits, including four unprecedented KAc mimetics. We solved the crystal structure of four hits, determined their binding mode, and improved their potency through synthesis and the purchase of derivatives. This work provides a validated virtual screening approach that is applicable to other BRDs and describes novel KAc mimetics that can be further explored to design more potent inhibitors.
- Vidler, Lewis R.,Filippakopoulos, Panagis,Fedorov, Oleg,Picaud, Sarah,Martin, Sarah,Tomsett, Michael,Woodward, Hannah,Brown, Nathan,Knapp, Stefan,Hoelder, Swen
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Read Online
- Selective Monomethylation of Amines with Methanol as the C1 Source
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The N-monomethyl functionality is a common motif in a variety of synthetic and natural compounds. However, facile access to such compounds remains a fundamental challenge in organic synthesis owing to selectivity issues caused by overmethylation. To address this issue, we have developed a method for the selective, catalytic monomethylation of various structurally and functionally diverse amines, including typically problematic primary aliphatic amines, using methanol as the methylating agent, which is a sustainable chemical feedstock. Kinetic control of the aliphatic amine monomethylation was achieved by using a readily available ruthenium catalyst at an adequate temperature under hydrogen pressure. Various substrates including bio-related molecules and pharmaceuticals were selectively monomethylated, demonstrating the general utility of the developed method.
- Choi, Geunho,Hong, Soon Hyeok
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supporting information
p. 6166 - 6170
(2018/04/30)
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- Design, synthesis, and biological evaluation of a series of resorcinol-based N-benzyl benzamide derivatives as potent Hsp90 inhibitors
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Heat shock protein 90 (Hsp90) is a ubiquitous molecular chaperone that is responsible for the stabilization and maturation of many oncogenic proteins. Therefore, Hsp90 has emerged as an attractive target in the field of cancer chemotherapy. In this study, we report the design, synthesis, and biological evaluation of a series of Hsp90 inhibitors. In particular, compound 30f shows a significant Hsp90α inhibitory activity with IC50 value of 5.3 nM and an excellent growth inhibition with GI50 value of 0.42 μM against non-small cell lung cancer cells, H1975. Compound 30f effectively reduces the expression levels of Hsp90 client proteins including Her2, EGFR, Met, Akt, and c-Raf. Consequently, compound 30f promotes substantial cleavages of PARP, Caspase 3, and Caspase 8, indicating that 30f induces cancer cell death via apoptotic pathway. Moreover, cytochrome P450 assay indicates that compound 30f has weak inhibitory effect on the activities of five major P450 isoforms (IC50 > 5 μM for 1A2, 2C9, 2C19, 2D6, and 3A), suggesting that clinical interactions between 30f and the substrate drugs of the five major P450 isoforms are not expected. Compound 30f also inhibits the tumor growth in a mouse xenograft model bearing subcutaneous H1975 without noticeable abnormal behavior and body weight changes. The immunostaining and western immunoblot analysis of EGFR, Met, Akt in xenograft tissue sections of tumor further demonstrate a good agreement with the in vitro results.
- Park, Sun You,Oh, Yong Jin,Lho, Yunmee,Jeong, Ju Hui,Liu, Kwang-Hyeon,Song, Jaeyoung,Kim, Soong-Hyun,Ha, Eunyoung,Seo, Young Ho
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p. 390 - 401
(2017/12/07)
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- Selective synthesis of mono- and di-methylated amines using methanol and sodium azide as C1 and N1 sources
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A Ru(ii) complex mediated synthesis of various N,N-dimethyl and N-monomethyl amines from organic azides using methanol as a methylating agent is reported. This methodology was successfully applied for a one-pot reaction of bromide derivatives and sodium azide in methanol. Notably, by controlling the reaction time several N-monomethylated and N,N-dimethylated amines were synthesized selectively. The practical applicability of this tandem process was revealed by preparative scale reactions with different organic azides and synthesis of an anti-vertigo drug betahistine. Several kinetic experiments and DFT studies were carried out to understand the mechanism of this transformation.
- Chakrabarti, Kaushik,Mishra, Anju,Panja, Dibyajyoti,Paul, Bhaskar,Kundu, Sabuj
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supporting information
p. 3339 - 3345
(2018/07/29)
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- Tandem C(sp3)?H Arylation/Oxidation and Arylation/Allylic Substitution of Isoindolinones
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Isoindolinones comprise an important class of medicinally active compounds. Herein we report a straightforward functionalization of isoindolinones with aryl bromides (22 examples) using a palladium(II) acetate/NIXANTPHOS-based catalyst system. Additionally 3-aryl-3-hydroxyisoindolinone derivatives, which exhibit anti-tumor activity, can be accessed via a tandem reaction. Thus, when the arylation product is exposed to air under basic conditions, in situ oxidation takes place to install the 3-hydroxy group. Furthermore, a tandem arylation/allylic substitution reaction is advanced in which both the arylation and allylic substitution are catalyzed by the same palladium catalyst. Finally, a tandem arylation/alkylation procedure is presented. These tandem reactions enable the synthesis of a variety of structurally diverse isoindolinone derivatives from common starting materials. (Figure presented.).
- Jiménez, Jacqueline,Kim, Byeong-Seon,Walsh, Patrick J.
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supporting information
p. 2829 - 2837
(2016/09/13)
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- 4-Phenyl tetrahydroisoquinolines as dual norepinephrine and dopamine reuptake inhibitors
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Novel 4-phenyl tetrahydroisoquinolines that inhibit both dopamine and norepinephrine transporters were designed and prepared. In this Letter, we describe the synthesis, in vitro activity and associated structure-activity relationships of this series. We also report the ex vivo NET occupancy of a representative compound, 41.
- Pechulis, Anthony D.,Beck, James P.,Curry, Matt A.,Wolf, Mark A.,Harms, Arthur E.,Xi, Ning,Opalka, Chet,Sweet, Mark P.,Yang, Zhicai,Vellekoop, A. Samuel,Klos, Andrew M.,Crocker, Peter J.,Hassler, Carla,Laws, Mia,Kitchen, Douglas B.,Smith, Mark A.,Olson, Richard E.,Liu, Shuang,Molino, Bruce F.
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p. 7219 - 7222
(2013/01/15)
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- Highly enantioselective synthesis of tetrahydroquinolines via cobalt(II)-catalyzed tandem 1,5-hydride transfer/cyclization
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A chiral catalyst prepared from N,N′-dioxide and Co(BF 4)2·6H2O was applied in the asymmetric hydride transfer initiated cyclization reaction, giving optically active tetrahydroquinolines in good yields with high enantioselectivities under mild reaction conditions. Meanwhile, in light of the absolute configuration of the product, a possible working model was proposed to explain the origin of the activation and asymmetric induction.
- Cao, Weidi,Liu, Xiaohua,Wang, Wentao,Lin, Lili,Feng, Xiaoming
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supporting information; scheme or table
p. 600 - 603
(2011/04/15)
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- NOVEL PROTEIN TYROSINE PHOSPHATASE - IB INHIBITORS
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The present invention relates to the novel compounds of the general formula (I), wherein the symbols are same as described in specification, their pharmaceutically acceptable salts, their tautomeric forms, their stereoisomers, pharmaceutical compositions containing them, to process and intermediates for the preparation of the above said compounds, having the utility of these compounds in medicine and to methods for their therapeutic use, and their use in the treatment of diabetes and related diseases.
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Page/Page column 50
(2009/10/22)
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- NOVEL PROTEIN TYROSINE PHOSPHATASE - IB INHIBITORS
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The present invention relates to the novel compounds of the general formula (I), wherein the symbols are same as described in specification, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, to process and intermediates for the preparation of the above said compounds, having the utility of these compounds in medicine and to methods for their therapeutic use, and their use in the treatment of metabolic disorders.
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Page/Page column 70
(2009/10/22)
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- Antimycobacterial activity of new 3,5-disubstituted 1,3,4-oxadiazol-2(3H)-one derivatives. Molecular modeling investigations
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3H-1,3,4-Oxadiazol-2-one derivatives were synthesized and tested for their in vitro antimycobacterial activity. Oxadiazolone derivatives showed an interesting antimycobacterial activity against the reference strain of Mycobacterium tuberculosis H37Rv. Molecular modeling investigations were performed and showed that the active compounds possess all necessary features to target the protein active site of the mycobacterial cytochrome P450-dependent sterol 14α-demethylase in the sterol biosynthesis pathway as the calculated free energy of binding were in agreement with the corresponding MIC values.
- Zampieri, Daniele,Mamolo, Maria Grazia,Laurini, Erik,Fermeglia, Maurizio,Posocco, Paola,Pricl, Sabrina,Banfi, Elena,Scialino, Giuditta,Vio, Luciano
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experimental part
p. 4693 - 4707
(2009/10/24)
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- Novel pyrrolidine ureas as C-C chemokine receptor 1 (CCR1) antagonists
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Monocyte infiltration is implicated in a variety of diseases including multiple myeloma, rheumatoid arthritis, and multiple sclerosis. C-C chemokine receptor 1 (CCR1) is a chemokine receptor that upon stimulation, particularly by macrophage inflammatory protein 1a (MIP-1a) and regulated on normal T-cell expressed and secreted (RANTES), mediates monocyte trafficking to sites of inflammation. High throughput screening of our combinatorial collection identified a novel, moderately potent CCR1 antagonist 3. The library hit 3 was optimized to the advanced lead compound 4. Compound 4 inhibited CCR1 mediated chemotaxis of monocytes with an IC50 of 20 nM. In addition, the compound was highly selective over other chemokine receptors. It had good microsomal stability when incubated with rat and human liver microsomes and showed no significant cytochrome P450 (CYP) inhibition. Pharmacokinetic evaluation of the compound in the rat showed good oral bioavailability.
- Merritt, J. Robert,Liu, Jinqi,Quadros, Elizabeth,Morris, Michelle L.,Liu, Ruiyan,Zhang, Rui,Jacob, Biji,Postelnek, Jennifer,Hicks, Catherine M.,Chen, Weiqing,Kimble, Earl F.,Rogers, W. Lynn,O'Brien, Linda,White, Nicole,Desai, Hema,Bansal, Shalini,King, George,Ohlmeyer, Michael J.,Appell, Kenneth C.,Webb, Maria L.
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supporting information; experimental part
p. 1295 - 1301
(2009/12/07)
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- Formation of benzylamines from triazene compounds via a 1,2-proton shift
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A new approach to benzylamines using triazene compounds has been developed that is facilitated by the lithiation of aryltriazenes followed by treatment with an electrophile. The regioselectivity of the reaction can be controlled by means of the substituents in the aryl group. The reaction contains the following steps: intramolecular carbon-carbon bond formation involving lithiation of an alkyl group on a 3-nitrogen atom; a 1,2-proton shift; and the subsequent release of nitrogen gas. Through the use of a deuterated triazene, we were able to determine that the reaction proceeds through a 1,2-proton shift.
- Nishiwaki, Keiji,Ogawa, Takashi,Shigeta, Kazumi,Takahashi, Koichi,Matsuo, Keizo
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p. 7034 - 7042
(2007/10/03)
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- TACHYKININ RECEPTOR ANTAGONISTS
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The present invention relates to selective NK-1 receptor antagonists of Formula (I) or a pharmaceutically acceptable salt thereof, for the treatment of disorders associated with an excess of tachykinins.
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- Oxidation of secondary amines by molecular oxygen and cyclohexanone monooxygenase
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Cyclohexanone monooxygenase from Acinetobacter calcoaceticus catalyzed the oxidation of tertiary and secondary amines to N-oxides and nitrones, respectively. The formation of a hydroxylamine intermediate was involved with secondary amines as starting substrates.
- Colonna, Stefano,Pironti, Vincenza,Carrea, Giacomo,Pasta, Piero,Zambianchi, Francesca
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p. 569 - 575
(2007/10/03)
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- α-lithiation of 1-Aryl-3,3-dialkyltriazenes and intramolecular conversion to benzylamine and tetrahydrobenzotriazine derivatives
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An alternative route to benzylamine derivatives is provided by the lithiation of aryltriazenes followed by treatment with an electrophile [Eq. (1)]. The regioselectivity of the reaction can be controlled by means of the substituents X. When the 2- and 6-p
- Nishiwaki, Keiji,Ogawa, Takashi,Matsuo, Keizo
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p. 484 - 486
(2007/10/03)
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- β-lactam derivatives as inhibitors of human cytomegalovirus protease
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The development of novel monobactam inhibitors of HCMV protease incorporating a carbon side chain at C-4 and a urea function at N-1 is described. Substitution with small groups at the C-3 position of the β- lactam ring gave an increase in enzymatic activity and in stability; however, a lack of selectivity against other serine proteases was noted. The use of both triand tetrasubstituted urea functionalities gave effective inhibitors of HCMV protease. Benzyl substitution of the urea moiety was beneficial, especially when strong electron-withdrawing groups where attached at the para position. Modest antiviral activity was found in a plaque reduction assay.
- Yoakim, Christiane,Ogilvie, William W.,Cameron, Dale R.,Chabot, Catherine,Guse, Ingrid,Haché, Bruno,Naud, Julie,O'Meara, Jeff A.,Plante, Raymond,Déziel, Robert
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p. 2882 - 2891
(2007/10/03)
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- Practical and efficient synthesis of C2 symmetrical diamines with Zn / Me3SiCl
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C2 symmetrical diamines are efficiently obtained by reductive coupling of imines with the couple Zn/Me3SiCl. This high yielding method is very practical and cheap for large scale preparation.
- Alexakis, Alexandre,Aujard, Isabelle,Mangeney, Pierre
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p. 873 - 874
(2007/10/03)
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- Isomerization of meso diamines into their C2 symmetrical d,l isomers
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An efficient isomerization method is disclosed which allows the obtention of the useful d,l isomers of C2 symmetrical diamines, starting from their meso isomer.
- Alexakis, Alexandre,Aujard, Isabelle,Mangeney, Pierre
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p. 875 - 876
(2007/10/03)
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- 3(2H)pyridazinone, process for its preparation and anti-allergic agent containing it
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A 3(2H)pyridazinone of the formula: STR1 wherein R1 is C2 -C5 alkyl; R2 is hydrogen, C1 -C3 alkyl, chlorine or bromine; R3 is hydrogen or C1 -C4 alkyl; and each of Y1, Y2 and Y3 which may be the same or different, is hydrogen, C1 -C8 alkyl, C2 -C8 alkenyl, halogen, --(CH2)l A [wherein A is substituted amino of the formula --N(R4) (R5) (wherein each of R4 and R5 which may be the same or different, is C1 -C4 alkyl, or R4 and R5 together form C4 -C6 alkylene), morpholino, 4-R6 -piperazin-1-yl (wherein R6 is C1 -C3 alkyl) or --OR7 (wherein R7 is hydrogen or C1 -C3 alkyl), and l is an integer of 0 to 3], --OR8 [wherein R8 is hydrogen, C1 -C8 alkyl, C3 -C5 alkenyl, benzyl or --(CH2)q --R9 [wherein R9 is CO2 R3 (wherein R3 is as defined above), --CONHR3 (wherein R3 is as defined above) or --CH2 OR7 (wherein R7 is as defined above), and q is an integer of 1 to 5]], --CO2 R3 (wherein R3 is as defined above), --CON(R10) (R11) [wherein each of R10 and R11 which may be the same or different, is hydrogen, C1 -C4 alkyl or C3 -C5 alkenyl, or R10 and R11 together form C4 -C6 alkylene, --(CH2)2 O(CH2)2 -- or --(CH2)2 N(R6)(CH2)2 -- (wherein R6 is as defined above)], --CONH(CH2)m A (wherein A is as defined above, and m is an integer of 2 to 4), --CH=CHCOR12 (wherein R12 is hydroxy, C1 -C4 alkoxy or --N(R13) (CH2)n CO2 R3 (wherein R13 is hydrogen, C1 -C6 alkyl or cycloalkyl, R3 is as defined above, and n is an integer of 1 to 4)), --SR14 (wherein R14 is C1 -C4 alkyl), --CN or STR2 wherein R3 is as defined above), or two of Y1, Y2 and Y3 together form STR3 (wherein p is an integer of 1 or 2), and a pharmaceutically acceptable salt thereof.
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- Cross Interaction Constants As a Measure of Transition State structure. Part 7. Aminolysis of Alkyl Benzenesulphonates
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Kinetic studies of the reactions of methyl and ethyl benzenesulphonates with anilines and benzylamines in methanol and acetonitrile at 65.0 deg C have been reported.The magnitudes of cross-interaction constants between substituents in the nucleophile (X) and the leaving group (Z),ρxz and βxz, were found to be greater for the ethyl series which indicates a tighter transition state for ethyl rather than methyl derivatives.This unexpected trend has been rationalized by making the assumption that the small electron-donating polar effect, of the α-methyl substituent in the ethyl compounds, requires a tighter transition-state structure in addition to the major effect of steric repulsion on the activation barrier which is present in all SN2 reactions taking place at a carbon centre.
- Lee, Ikchoon,Choi, Young Hoon,Rhyu, Keun Woo,Shim, Chang Sub
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p. 1881 - 1886
(2007/10/02)
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- Oxidations with Cerium(IV) Sulfate: Intramolecular Cyclization of N-Benzyl-&β-aminoketones Yielding 4-Benzoyl-1,2,3,4-tetrahydroisoquinolines
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Preparation and regiospecific cerium(IV) sulfate of the substituted N-benzyl-β-aminoketones 3 are described. 4-Benzoyl-1,2,3,4-tetrahydroisoquinolines 4 so obtained are reduced by sodium borohydride.
- Holzgrabe, Ulrike
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p. 647 - 654
(2007/10/02)
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- Quantitative structure-activity relationship of the mutagenicity of substituted N-nitroso-N-benzylmethylamines: Possible implications of carcinogenicity
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The relative mutagenicities of substituted N-nitroso-N-benzylmethylamines have been reexamined from a quantitative structure-activity relationship point of view. Most of the compounds were mutagenic toward Salmonella typhimurium TA 1535 with Aroclor-induced male hamster liver S9 activation. The dose-response data were subjected to a multiple linear regression equation calculated in a stepwise manner, which found that the differences in mutagenicities could be explained primarily by differences in the three-bond path molecular connectivity index, with smaller contributions from σ and π. Moreover, a polynomial regression analysis showed that the maximum mutagenicity could be explained by an optimal amount of electron withdrawal by the substituent which could cause a weakening, or activation, of the methylene C-H bond. The possible relevance of these observations to carcinogenesis is discussed.
- Singer,Andrews,Guo
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- Oxidative N-Dealkylation of N,N-Dimethylbenzylamines by Metalloporphyrin-catalysed Model Systems for Cytochrome P450 Mono-oxygenases
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Iodosylbenzene, catalysed by tetraphenylporphyrinato-iron(III) or - manganese(III) chloride, oxidises tertiary amines by an initial one-electron transfer process whereas with t-butyl hydroperoxide with these catalysts the oxidation is initiated by hydrogen atom abstraction.
- Smith, John R. Lindsay,Mortimer, David N.
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- Mutagenicity and Chemistry of N-Nitroso-N-(p-substituted-benzyl)methylamines
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The relative mutagenicities of N-nitroso-N-(p-substituted-benzyl)methylamines in Salmonella typhimurium TA 1535 were tested in order to determine whether biological activity is affected by the electron density at a nitrosamine α carbon.The order of potency was as follows: X = Cl > CN > Br > NO2 > H > CH3O > CH3 > F >> COOH.No direct correlation was apparent, nor was there obvious correlation between biological activity and the extent of base-catalysed hydrogen-deuterium exchange at the α-carbons.
- Singer, George M.,Andrews, A.W.
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p. 309 - 312
(2007/10/02)
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- Substituted 7,12-methano dibenzazocines
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Substituted 7,12-methano-dibenzazocines, e.g., 7,13-dihydro-6,12-dimethyl-7,12-methano-6H-dibenz[c,f]azocine, are prepared by cyclizing 3-benzylamino-alkyl-indan-1-ols and are useful as anti-inflammatory agents.
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- Substituted 7,12-methano dibenzazocines and 8,13-methano dibenzazonines
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Substituted 7,12-methano-dibenzazocines and 8,13-methanodibenzazonines, e.g., 7,12-dihydro-6,13-dimethyl-7,12-methano-6H-dibenz [c,f] azocine, are prepared by cyclizing 3-benzylamino or 3-phenethylamino -2-alkyl-indan-1-ols and are useful as anti-inflammatory agents.
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