- Direct amidation to access 3-amido-1,8-naphthalimides including fluorescent scriptaid analogues as hdac inhibitors
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Methodology to access fluorescent 3-amido-1,8-naphthalimides using direct Buchwald– Hartwig amidation is described. The protocol was successfully used to couple a number of substrates (including an alkylamide, an arylamide, a lactam and a carbamate) to 3-bromo-1,8-naphthalimide in good yield. To further exemplify the approach, a set of scriptaid analogues with amide substituents at the 3-position were prepared. The new compounds were more potent than scriptaid at a number of histone deacetylase (HDAC) isoforms including HDAC6. Activity was further confirmed in a whole cell tubulin deacetylation assay where the inhibitors were more active than the established HDAC6 selective inhibitor Tubastatin. The optical properties of these new, highly active, compounds make them amenable to cellular imaging studies and theranostic applications.
- Hearn, Kyle N.,Ashton, Trent D.,Acharya, Rameshwor,Feng, Zikai,Gueven, Nuri,Pfeffer, Frederick M.
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- Synthesis and photophysical properties of blue-emitting fluorescence dyes derived from naphthalimide derivatives containing a diacetylene linkage group
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Four naphthalimide-based dyes with a diacetylene linkage at the 3- or 4-position were synthesized to improve the thermal stability of the fluorescence dye as well as the efficiency of fluorescent emission at blue region. The absorption and fluorescence properties of the synthesized dyes were also investigated. The geometries and molecular orbitals of the dyes prepared were simulated using by density functional theory and time-dependent density functional theory using Gaussian 09. Furthermore, the suitability of the dyes for application in light-conversion films was examined. N-Phenyl groups were found to have a greater effect on the fluorescence of naphthalimide-based dyes than analogue containing an N-alkyl group. In addition, investigation of the effect of diacetylene linkages at the 3- or 4-positions of naphthalimide-based dyes showed that the fluorescence was influenced by the electron-donating effect of the diacetylene linkage which could afford more conjugation of π orbitals of the dyes. Four blue fluorescence dyes derived from 1,8-naphthalimide containing a diacetylene linkage were synthesized and then coated in PE film. The photophysical properties were analyzed using density functional theory (DFT) calculations, and excitations from the highest occupied molecular orbitals (HOMOs) to the lowest unoccupied molecular orbitals (LUMOs) of the dyes were simulated at the B3LYP/6-31G level of theory via the Gaussian 09 suite of programs. Using these methods, the influences of the position of the ethynyl linkages, alkyl groups, and phenyl groups on the electronic and fluorescence properties of the dyes were also clarified.
- Kim, Kyung-Won,Kim, Geun-Hyeong,Kwon, Su-Hyeon,Yoon, Hyo-In,Son, Jung-Eek,Choi, Jae-Hong
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- Discovery of novel small molecule induced selective degradation of the bromodomain and extra-terminal (BET) bromodomain protein BRD4 and BRD2 with cellular potencies
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The BET proteins BRD2, BRD3, and BRD4 play important roles in transcriptional regulation and can be degraded by proteolysis-targeting chimeras (PROTACs) for BET proteins. However, the lack of intra-BET proteins selectivity limits the scope of current degraders as probes for target validation and could lead to unwanted side effects or toxicity in a therapeutic setting. We describe herein the design, synthesis, and evaluation of PROTAC BET degraders, based on the BET inhibitor with selectivity for the first Bromodomain benzo[cd]indole-2-one, alkylamide linker and cereblon ligand thalidomide. Compound 15 potently and rapidly induces reversible, long-lasting, and unexpectedly selective removal of BRD4 and BRD2 over BRD3, which not only effectively inhibits cell growth in human acute leukemia cell lines, but also very effective in inhibiting solid tumors with low cytotoxic effect in the cell profiles of NCI 60 cell lines. Remarkable dependency on linker length was observed for BRD4-degrading and c-Myc-driven antiproliferative activities in acute myeloid leukemia cell line MV4-11. The small-molecular 15 represents a novel, potent, and selective class of BRD4 and BRD2 degraders for the development of therapeutics to treat cancers.
- Cao, Peng,Chen, Haifang,Chen, Yadong,Cui, Yong,Jiang, Fei,Li, Hongmei,Li, Huili,Lu, Tao,Ma, Yu,Wei, Qingyun
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- Synthesis of new amonafide analogues via coupling reaction and their cytotoxic evaluation and DNA-binding studies
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A series of 5-alkylamino substituted amonafide analogues were synthesized from naphthalic anhydride by three steps including bromization, amination and CuI/proline catalyzed coupling reaction. The CuI/L-proline catalyzed coupling reaction was first applied to the naphthalimide system. These new amonafide analogues showed potential anticancer activities against HeLa and P388D1 cell lines in vitro, and 4a, 4b, and 4h exhibited better activity than amonafide against HeLa cell under the same experimental conditions. More importantly, the new analogues could avoid the side effect of amonafide due to their structure, in which lacks a primary amine at the 5 position. Moreover, the DNA-binding of the analogues was also investigated.
- Xie, Lijuan,Xu, Yufang,Wang, Fang,Liu, Jianwen,Qian, Xuhong,Cui, Jingnan
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- Benzoindole bifunctional molecular derivatives as well as preparation method and application thereof
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The invention belongs to the field of medical chemistry, and particularly relates to benzoindole bifunctional molecule derivatives as well as a preparation method and application thereof. The benzoindole bifunctional molecule of the derivative, or tautomer, mesomer, raceme, enantiomer, diastereomer, hydrate or pharmaceutically acceptable salt has a structure as shown in a general formula (I). Thederivative is a protein degradation targeting chimeric body (PROTACs) technology, and can induce the degradation of BET protein. The invention also discloses application of the bifunctional molecularcompound in medicines for preventing and/or treating BET protein related diseases.
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Paragraph 0102-0106
(2021/01/04)
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- Synthesis and photophysical properties of fluorescent dyes based on triphenylamine, diphenylamine, diphenyl sulfone or triphenyltriazine derivatives containing an acetylene linkage group
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In this study, ten fluorescent dyes were prepared based on three different kinds of central moiety, such as triphenylamine, diphenylsulfone or triphenyltriazine, which was coupled to either carbazole or naphthalimidinyl group via an acetylene linkage group. N-n-Butyl-carbazole, N-phenyl-carbazole or N-n-butyl-naphthalimide was coupled to the individual central moiety of triphenylamine, diphenyl sulfone, 2,4,6-triphenyl-1,3,5-trazine or diphenylamine using a Sonogashira coupling reaction in the final step. All dyes were confirmed their chemical structure by 1H NMR, GC-Mass and elemental analyses. The absorption properties and thermal stabilities of the fluorescent dyes were examined. Density Functional Theory (DFT) and Time-Dependent DFT calculations were carried out, in addition to geometry simulation, by using the Gaussian 09 program. In terms of fluorescence properties in this series, two dyes based on diphenyl sulfonyl and three dyes based on triphenylamine substituted by 1–3 of N-n-butyl-carbazole exhibited a blue emission, whereas three dyes based on triphenylamine substituted by 1–3 of N-n-butyl-naphthalimide were observed by a red emitter which can be attributable to both effects the bathochromic shifts in absorption maxima and larger Stokes shifts. In case of corresponding 2,4,6-triphenyl-1,3,5-trazine central moiety coupled to a carbazole ring, a green fluorescence was emitted. Results revealed that the fluorescence of the dyes is affected by the electron-donating strength of the acetylene linkages involved in the π-conjugation systems of the dyes.
- Ahn, Sung-Ok,Choi, Jae-Hong,Kim, Kyung-Won,Kwon, Su-Hyeon,Lee, Byung-Jun,Lee, Ju-Hong
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- Discovery of Benzo[ cd]indol-2(1 H)-ones and Pyrrolo[4,3,2- de]quinolin-2(1 H)-ones as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the First Bromodomain with Potential High Efficiency against Acute Gouty Arthritis
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The bromodomain and extra-terminal domain (BET) family of proteins are readers which specifically recognize histone-acetylated lysine residues. Each BET bromodomain protein contains two highly homologous domains: the first bromodomain (BD1) and the second bromodomain (BD2). Pan-BET bromodomain inhibition is a potential therapy for various cancers and immune-inflammatory diseases, but only few reported inhibitors show selectivity within the BET family. Herein, we identified a series of benzo[cd]indol-2(1H)-ones and pyrrolo[4,3,2-de]quinolin-2(1H)-ones with good selectivity for BET BD1. Through structure-based optimization, highly active and selective compounds are ultimately obtained. The representative compounds are the first reported inhibitors with selectivity more than 100-fold for BRD4(1) over BRD4(2). Among them, we further show that 68 (LT052) mediates BRD4/NF-κB/NLRP3 signaling inflammatory pathways with comparable protein expression and significantly improves symptoms of gout arthritis in a rat model. Therefore, selective pharmacological modulation of individual bromodomains could represent a strategy for the treatment of acute gouty arthritis.
- Jiang, Fei,Hu, Qinghua,Zhang, Zhimin,Li, Hongmei,Li, Huili,Zhang, Dewei,Li, Hanwen,Ma, Yu,Xu, Jingjing,Chen, Haifang,Cui, Yong,Zhi, Yanle,Zhang, Yanmin,Xu, Junyu,Zhu, Jiapeng,Lu, Tao,Chen, Yadong
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p. 11080 - 11107
(2019/12/24)
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- Expanding the Breadth of 4-Amino-1,8-naphthalimide Photophysical Properties through Substitution of the Naphthalimide Core
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Fluorescent sensors that illuminate specific molecules and chemical events allow the selective and sensitive study of the cellular environment. At the centre of this technology lies the fluorescent reporter molecule, and it is therefore crucial to provide a breadth of fluorophores with varying photophysical and biological behaviour. 4-Amino-1,8-naphthalimides are commonly employed in fluorescent sensors, but the narrow range of structural derivatives limits versatility of application. Here we report the synthesis and investigation of a set of twelve 4-amino-1,8-naphthalimides bearing an additional substituent on the aromatic core. Photophysical characterisation and time-dependent density functional theory studies provided insights into the structure–photophysical property relationships of these derivatives, which show an expanded range of emission wavelengths and other photophysical properties. These compounds could all be visualised within cells by confocal microscopy, showing cytoplasmic or lipid droplet localisation. Our studies have demonstrated that simple structural modification of 4-amino-1,8-naphthalimides provides derivatives with considerable breadth of behaviour that lend valuable versatility to the design of fluorescent sensors.
- Leslie, Kathryn G.,Jacquemin, Denis,New, Elizabeth J.,Jolliffe, Katrina A.
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supporting information
p. 5569 - 5573
(2018/03/21)
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- NOVEL EP2 RECEPTOR AGONISTS
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The compounds of formula (1), in which R1, R4, A and X have the meanings as given in the description, are novel effective EP2 agonists.
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Page/Page column 19
(2013/11/19)
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- Synthesis and characterization of 1,8-naphthalimide with [6]helicene skeleton
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A 1,8-naphthalimide with [6]helicene derivative scaffold has been designed and synthesized. The (P)- and (M)-enantiomers of the [6]helicene derivative were resolved by HPLC on a chiral column. The single crystal of the [6]helicene derivative exhibits an intermolecular interactions of the 1,8-naphthalimide units. The Royal Society of Chemistry 2012.
- Kogiso, Toshitaka,Yamamoto, Kosuke,Suemune, Hiroshi,Usui, Kazuteru
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supporting information; experimental part
p. 2934 - 2936
(2012/05/07)
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- COMPOUNDS FOR THE INHIBITION OF CELLULAR PROLIFERATION
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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, (4) disorders associated with viral infections, and/or (5) non-proliferative metabolic disorders such as type II diabetes where inhibition of translation initiation is beneficial using the compounds disclosed herein.
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Page/Page column 70-71
(2012/02/01)
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- Organometallic pyridylnaphthalimide complexes as protein kinase inhibitors
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A new metal-containing scaffold for the design of protein kinase inhibitors is introduced. The key feature is a 3-(2-pyridyl)-1,8-naphthalimide "pharmacophore chelate ligand", which is designed to form two hydrogen bonds with the hinge region of the ATP-b
- Blanck, Sebastian,Cruchter, Thomas,Vultur, Adina,Riedel, Radostan,Harms, Klaus,Herlyn, Meenhard,Meggers, Eric
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scheme or table
p. 4598 - 4606
(2011/11/28)
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- THIAZOLE DERIVATIVES AS SGLT2 INHIBITORS AND PHARMACEUTICAL COMPOSITION COMPRISING SAME
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The present invention relates to a novel compound with thiazole ring having an inhibitory activity against sodium-dependent glucose cotransporter 2 (SGLT2) being present in the intestine and kidney, and a pharmaceutical composition comprising the same as an active ingredient, which is useful for preventing or treating metabolic disorders, particularly diabetes.
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Page/Page column 54
(2012/01/06)
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- 5-Non-amino aromatic substituted naphthalimides as potential antitumor agents: Synthesis via Suzuki reaction, antiproliferative activity, and DNA-binding behavior
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Amonafide is a naphthalimide derivative with antitumor activity and has failed to enter clinical phase III, because of its high-variable and unpredictable toxicity. In order to develop selective, efficient, and safe drugs, applying the 'nonfused' aromatic
- Xie, Lijuan,Cui, Jingnan,Qian, Xuhong,Xu, Yufang,Liu, Jianwen,Xu, Ruian
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scheme or table
p. 961 - 967
(2011/03/17)
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- RENIN INHIBITORS
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Renin inhibitors, which are spirocyclic piperidine amides, of structural formula (I) and pharmaceutical compositions thereof useful in the treatment of cardiovascular diseases and renal insufficiency, wherein n, for each instance in which it occurs, is independently 0, 1, or 2; R1 is hydrogen, C1-6 -alkyl or C3-6 -cycloalkyl, wherein said C1-6 -alkyl or C3-6 -cycloalkyl group can be independently substituted with 1-3 halogens; A is (i) a five- or six-membered saturated or unsaturated heterocyclic or carbocyclic monocyclic ring or (ii) a five- or six-membered saturated or unsaturated heterocyclic or carbocyclic ring which is fused to another five- or six-membered saturated or unsaturated heterocyclic or carbocyclic ring, V is a bond or -(C=O)-, -CH(OH)-, -CH2- or =CH-; U is a bond or -CH2-, or for the case when V is =CH-, U is -CH=; X is =CH-, =CF-, =C(OR3)-, or -C=O-; and Y is =CH-, =CF-, =N-, or for the case when X is -C=O-, Y is -N(R3)-.
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Page/Page column 26
(2011/04/13)
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- NOVEL C-ARYL GLUCOSIDE SGLT2 INHIBITORS AND PHARMACEUTICAL COMPOSITION COMPRISING SAME
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A novel C-aryl glucoside compound, or a pharmaceutically acceptable salt or a prodrug thereof having an inhibitory activity against sodium-dependent glucose cotransporter 2 (SGLT2) being present in the intestine and kidney; and a pharmaceutical composition comprising the same as an active ingredient, which is useful for preventing or treating metabolic disorders, particularly, diabetes, are provided.
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Page/Page column 113
(2010/12/31)
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- METHODS OF MODULATING NEUROTROPHIN-MEDIATED ACTIVITY
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Disclosed are compositions which modulate the interaction with nerve growth factor and precursors thereof with neurotrophic receptors. Also disclosed are methods of using the compositions of the invention, including methods of administration.
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Page/Page column 46-47
(2009/04/24)
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- A rapid, large-scale synthesis of a potent cholecystokinin (CCK) 1R receptor agonist
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The development of a scalable synthesis of a potent cholecystokinin (CCK) IR receptor agonist is described. The focus on a rapid short-term delivery rather than longer-term development allowed for the preparation of multihundred gram quantities to support
- Kuethe, Jeffrey T.,Childers, Karla G.,Humphrey, Guy R.,Journet, Michel,Peng, Zhihui
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p. 1201 - 1208
(2013/01/03)
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- Synthesis, biological evaluation and molecular modelling studies of novel ACD- and ABD-ring steroidomimetics as inhibitors of CYP17
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Two novel classes of non-steroidal substrate mimetics were synthesised and examined for their potency as inhibitors of human CYP17. Selected compounds were tested for inhibition of hepatic CYP enzymes 3A4, 1A2, 2C9 and 2C19. The most promising compound 15
- Pinto-Bazurco Mendieta, Mariano A.E.,Negri, Matthias,Jagusch, Carsten,Hille, Ulrike E.,Mueller-Vieira, Ursula,Schmidt, Dirk,Hansen, Klaus,Hartmann, Rolf W.
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p. 267 - 273
(2008/09/17)
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- A new approach to rapid parallel development of four neurokinin antagonists. Part 2. Synthesis of ZD6021 cyano acid
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The manufacture of ZD6021 cyano acid (1) using a new project approach is described. Research Department processes were scaled up to 100 L if process safety anal robustness were not compromised; other factors were treated according to the new approach. By using this strategy, we were able to manufacture a key intermediate on sufficient scale to support delivery of 1 kg quantities of bulk drug within 6 months of the start of lab work.
- Moseley, Jonathan D.,Moss, William O.,Welham, Matthew J.,Ancell, Claire L.,Banister, John,Bowden, Sharon A.,Norton, Glenn,Young, Maureen J.
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- Isoquinolones
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Benzo[de]isoquinoline-1,3-dione of Formula or a pharmaceutically acceptable salt thereof wherein R is hydrogen or a protecting group typically used in the art for protecting alcohols and R1-R5are each independently chosen from H, Cl, Br, F, straight or branched alkyl C1-C8alkyl, C3-C8cycloalkyl, heterocycle or bridged heterocycle of 4-9 atoms containing 1-3 heteroatoms, —(CR′2)nOR6, —(CR′2)nN(R6)2, —(CR′2)nNR6COR7, —(CR′2)nNR6SO2OR7, —(CR′2)nNR6SO2N(R6)2, —(CR′2)nOSO2N(R6)2, —(CR′2)nCN, —(CR′2)n(NOR6)R7, NO2, CF3, —(CR′2)nSOmR7, —(CR′2)nSOmR7, —(CR′2)nCO2R6, —(CR′2)nCON(R6)2, Ph, and any two of R1-R5may form a substituted or unsubstituted ring of 5-7 total atoms having 0-2 heteroatoms are claimed which are selective inhibitors of bacterial DNA gyrase and DNA topoisomerase useful in antibacterial agents. Methods for their preparation and formulation as well as novel intermediates useful in the preparation of the final products are also claimed.
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