- JNK Inhibitor. Pharmaceutical compositions and uses thereof
-
Provided herein are compounds represented by the following formula (I), racemates, stereoisomers, tautomers, isotopically labels, solvates, polymorphs, nitrogen oxides or pharmaceutically acceptable salts thereof, which can be used as JNK inhibitors. A method for preparing a compound represented by formula (I), a pharmaceutical composition comprising a compound represented by formula (I), and (I), for the preparation of a medicament for the treatment of a disease treatable by inhibition JNK activity.
- -
-
Paragraph 0172-0175
(2021/11/27)
-
- Synthesis and biological evaluation of the first dual tyrosyl-DNA phosphodiesterase i (Tdp1)-topoisomerase i (Top1) inhibitors
-
Substances with dual tyrosyl-DNA phosphodiesterase I-topoisomerase I inhibitory activity in one low molecular weight compound would constitute a unique class of anticancer agents that could potentially have significant advantages over drugs that work against the individual enzymes. The present study demonstrates the successful synthesis and evaluation of the first dual Top1-Tdp1 inhibitors, which are based on the indenoisoquinoline chemotype. One bis(indenoisoquinoline) had significant activity against human Tdp1 (IC 50 = 1.52 ± 0.05 μM), and it was also equipotent to camptothecin as a Top1 inhibitor. Significant insights into enzyme-drug interactions were gained via structure-activity relationship studies of the series. The present results also document the failure of the previously reported sulfonyl ester pharmacophore to confer Tdp1 inhibition in this indenoisoquinoline class of inhibitors even though it was demonstrated to work well for the steroid NSC 88915 (7). The current study will facilitate future efforts to optimize dual Top1-Tdp1 inhibitors.
- Nguyen, Trung Xuan,Morrell, Andrew,Conda-Sheridan, Martin,Marchand, Christophe,Agama, Keli,Bermingam, Alun,Stephen, Andrew G.,Chergui, Adel,Naumova, Alena,Fisher, Robert,O'Keefe, Barry R.,Pommier, Yves,Cushman, Mark
-
scheme or table
p. 4457 - 4478
(2012/08/07)
-
- OXOBENZINDOLIZINOQUINOLINES AND USES THEREOF
-
The synthesis of aromathecins, substituted 12H-5,l la-diazadibenzo[b,h]fluoren- 11 -ones is described. Use of these cytotoxic compounds and pharmaceutical compositions containing them for the treatment of cancer is described. Two novel processes for the synthesis of this system and a series of 14-substituted aromathecins as novel cytotoxic, topoisomerase I poisons are described.
- -
-
Page/Page column 42
(2009/12/23)
-
- Synthesis and biological evaluation of 14-(aminoalkyl-aminomethyl)aromathecins as topoisomerase I inhibitors: Investigating the hypothesis of shared structure-activity relationships
-
The aromathecin topoisomerase I (top1) inhibitors offer promising scaffolds for the development of novel cancer chemotherapeutics. They are 'composites' of the camptothecin and indenoisoquinoline top1 inhibitors. Interestingly, some structure-activity relationship (SAR) overlap between the aromathecins and the indenoisoquinolines has been observed. For both classes, placement of certain polar groups in similar regions of the heteroaromatic system improves top1 inhibitory and antiproliferative activities. A series of water-soluble aromathecins substituted at position 14 with diaminoalkanes of various lengths has been prepared. These compounds all possess similar antiproliferative potency, but a general trend is observed: aromathecins with longer diaminoalkane substituents (>6 carbons) possess lower anti-top1 activity than their smaller counterparts (2-4 carbons), presumably as a result of unfavorable hydrophobic interactions. This trend is also noted with the indenoisoquinolines, revealing additional SAR overlap that supports the hypothesis that there is a 'universal' top1 inhibitor SAR.
- Cinelli, Maris A.,Cordero, Brenda,Dexheimer, Thomas S.,Pommier, Yves,Cushman, Mark
-
experimental part
p. 7145 - 7155
(2010/03/01)
-
- Parallel synthesis and cytotoxicity evaluation of a polyamine-quinone conjugates library
-
A library of 24 derivatives designed by combining two natural products-derived fragments was prepared and tested to determine their anticancer potential in HT29 colon cancer cells. All library members inhibit cell proliferation as measured by MTT mitochondrial functional assay, with IC 50 values in the 1-100 μM range. Entry 1b caused apoptotic EGFR-mediated intracellular signaling. Thus, polyamino-quinones emerged as readily accessible and easily diversified scaffolds for anticancer lead discovery.
- Bolognesi, Maria Laura,Calonghi, Natalia,Mangano, Chiara,Masotti, Lanfranco,Melchiorre, Carlo
-
supporting information; experimental part
p. 5463 - 5467
(2009/07/01)
-
- N-SUBSTITUTED INDENOISOQUINOLINES AND SYNTHESES THEREOF
-
N-Substituted indenoisoquinoline compounds, and pharmaceutical formulations of N-substituted indenoisoquinoline compounds are described. Also described are processes for preparing N-substituted indenoisoquinoline compounds. Also described are methods for
- -
-
Page/Page column 40
(2008/06/13)
-
- Investigation of the lactam side chain length necessary for optimal indenoisoquinoline topoisomerase I inhibition and cytotoxicity in human cancer cell cultures
-
Indenoisoquinolines with lactam substituents such as ethylamino, propylamino, and butylamino have previously demonstrated potent biological activity, but an optimal length has never been established. In the present study, a series of simplified indenoisoquinoline analogues possessing a linker spacing of 0-12 carbon atoms between the lactam nitrogen and the terminal amino group have been prepared, determining that 2-4-atom lengths are optimal for topoisomerase I inhibition and cytotoxicity. Using these lengths, analogues were prepared with the amino group and portions of the linker replaced by a pyridine ring. A three-carbon spacer within the pyridine series still demonstrated potent topoisomerase I inhibition.
- Morrell, Andrew,Placzek, Michael S.,Steffen, Jamin D.,Antony, Smitha,Agama, Keli,Pommier, Yves,Cushman, Mark
-
p. 2040 - 2048
(2008/02/01)
-
- Synthesis and pharmacological studies of new hybrid derivatives of fentanyl active at the μ-opioid receptor and I2-imidazoline binding sites
-
Two series of fentanyl-derived hybrid molecules bearing potent I2-imidazoline binding site (IBS) ligands (i.e., guanidine and BU224 moieties) linked with an aliphatic (m = 2, 3, 4, 6, 7, 8, 9 and 12 methylene units) or aromatic spacer were prepared. Their affinities for the μ-opioid receptors and for the I2-IBS were determined through competition binding studies on human postmortem brain membranes. Whereas the BU224 hybrid molecules bound to the μ-opioid receptor and the I2-IBS in the micromolar to low micromolar range, the alkaneguanidine series exhibited remarkable affinities in the nanomolar range for both receptors. [35S]GTPγS functional assays were performed on human postmortem brain membranes with selected ligands from each series (4f and 8g) showing the highest dual affinity for the μ-opioid receptor and I2-IBS affinities. Both compounds displayed agonist properties: at the μ-opioid receptor for the alkaneguanidine derivative 4f (spacer: six methylene units) and at a G-protein coupled receptor (GPCR) which remains to be determined for 8g. The lack of analgesic properties of 4f in vivo (i.e., hot plate and writhing tests in mice), discordant with the good in vitro binding data (Ki μ = 1.04 ± 0.28 nM, Ki I2 = 409 ± 238 nM), may possibly be due to the low intrinsic efficacy of the compound. Alternatively, a low access to the central nervous system for this kind of hybrid molecules cannot be ruled out. Two new compounds reported here (9f and 13), which were not dual acting, are worth mentioning for their outstanding binding affinities; 9f bound to the μ-opioid receptor with a picomolar affinity (Ki = 0.0098 ± 0.0033 nM), whereas 13 presented an I2-IBS affinity (Ki = 18 ± 11 nM) similar to the reference compound BU224.
- Dardonville, Christophe,Fernandez-Fernandez, Cristina,Gibbons, Sarah-Louise,Ryan, Gary J.,Jagerovic, Nadine,Gabilondo, Ane M.,Meana, J. Javier,Callado, Luis F.
-
p. 6570 - 6580
(2007/10/03)
-
- Synthesis of dimeric acridine derived nucleic acid intercalators
-
A series of antiviral compounds consisting of an intercalating acridine derived part, a spacer region and a reactive EDTA-derived conjugate was synthesized in an easy sequence. Suitably monoprotected 1,ω-alkyldiamines gave upon reaction with 6,9-dichloro-2-methoxyacridine (1) followed by deprotection and reaction with EDTA dianhydride the target molecules. In the presence of ascorbate a reduction of the phage-titer of the MS2 phages by > 8 logarithmic decades was achieved.
- Csuk, René,Brezesinski, Thorsten,G?the, Gunnar,Raschke, Christian,Rei?mann, Stefan
-
-
- AMINE COMPOUNDS AND USE THEREOF
-
It is intended to provide novel amine compounds which are efficacious against diseases such as infection with HIV virus, rheumatism and cancer metastasis. Namely, amine compounds represented by the following general formula (1):In a typical case, A1 and A2 represent each an optionally substituted monocyclic or polycyclic aromatic heterocycle; W represents cyclic C3-10 alkylene, an optionally substituted monocyclic or polycyclic aromatic heterocycle, a monocyclic or polycyclic aromatic ring or a partly saturated polycyclic aromatic ring; X represents O, CH2, C(=O) or NR11; and D is a group represented by the following general formula (4) or (6).-Q-Y-BIn the formula (6), Q represents a single bond, S, O or NR12; and Y is a group represented by the following general formula (7). z represents an optionally substituted monocyclic or polycyclic aromatic ring. In the formula (6), B represents NR25R26. In the above formulae, R1 to R26 each represents hydrogen, alkyl, alkenyl or alkynyl.
- -
-
Page/Page column 71
(2010/02/12)
-
- Synthesis of pathogen inactivating nucleic acid intercalators
-
A series of antiviral compounds consisting of an intercalating acridine derived part, a spacer region and a reactive EDTA-derived conjugate was synthesized in an easy sequence starting from 1,ω-alkyldiamines. As shown in model screenings, in the presence of ascorbic acid the Fe-complexes of these compounds reduced the phage-titer of MS2-phages by several logarithmic decades.
- Csuk, René,Barthel, Alexander,Brezesinski, Thorsten,Raschke, Christian
-
p. 975 - 988
(2007/10/03)
-
- SULFONAMIDE DERIVATIVES OF 3-SUBSTITUTED IMIDAZOL[1,2-D] -1,2,4-THIADIAZOLES AND 3-SUBSTITUTED-[1,2,4] THIADIAZOLO[4,5-A] BENZIMIDAZOLE AS INHIBITORS OF FIBRIN CROSS-LINKING AND TRANSGLUTAMINASES
-
A method of inhibiting the activity of transglutaminases containing a cysteine residue comprising administering to a mammal an effective amount of a sulfonamide derivative of imidazo[1,2-d]-1,2,4-thiadiazoles sufficient to inhibit the activity
- -
-
-
- Sulfonamide derivatives of 3-substituted imidazo[1,2-D]-1,2,4-thiadiazoles and 3-substituted-[1,2,4]thiadiazolo[4,5-A]benzimidazole as inhibitors of fibrin cross-linking and transglutaminases
-
A method of inhibiting the activity of transglutaminases containing a cysteine residue comprising administering to a mammal an effective amount of a sulfonamide derivative of imidazo[1,2-d]-1,2,4-thiadiazoles sufficient to inhibit the activity.
- -
-
Page/Page column 24
(2008/06/13)
-
- COMB COPOLYMERS WITH THERMOTROPIC AND LYOTROPIC PROPERTIES SYNTHESIS AND STRUCTURAL STUDY
-
Comb copolymers with polyacrylamide or polymethacrylamide main chains and lipopeptidic side chains were synthesized in two steps: synthesis of a polymerizable lipopeptide followed by radical polymerization of the lipopeptidic macromonomer.X ray diffraction and DSC studies showed that comb copolymers exhibit both a thermotropic and a lyotropic behaviour.The influence of the nature and the degree of polymerization of the peptidic chains on the type (smectic, nematic or cholesteric) and the domain of stability of the liquid-crystalline structures was established.In the case of smectic structures, the influence of the solvent concentration and the degree of polymerization of the peptidic chains on the distances between the smectic planes was also established.
- Gallot, Bernard,Douy, Andre
-
p. 367 - 374
(2007/10/02)
-