- Metabolomics-assisted discovery of a new anticancer GLS-1 inhibitor chemotype from a nortopsentin-inspired library: From phenotype screening to target identification
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The enzyme glutaminase-1 (GLS-1) has shown a clear and coherent implication in the progression and exacerbation of different aggressive tumors such as glioblastoma, hepatocarcinoma, pancreas, bone, and triple-negative breast cancer. Few chemotypes are currently available as selective GLS-1 inhibitors, and still, fewer of them are at the clinical stage. In the present paper, starting from a naturally-inspired antitumor compound library, metabolomics has been used to putatively identify the molecular mechanism underlying biological activity. GLS-1 was identified as a potential target. Biochemical analysis confirmed the hypothesis leading to the identification of a new hit compound acting as a GLS-1 selective inhibitor (IC50 = 3.96 ± 1.05 μM), compared to the GLS-2 isoform (IC50 = 12.90 ± 0.87 μM), with remarkable antitumor potency over different aggressive tumor cell lines. Molecular modelling studies revealed new insight into the drug-target interaction providing robust SAR clues for the rational hit-to-lead development. The approach undertaken underlines the wide potential of metabolomics applied to drug discovery, particularly in target identification and hit discovery following phenotype screening.
- Carbone, Daniela,Vestuto, Vincenzo,Ferraro, Maria Rosalia,Ciaglia, Tania,Pecoraro, Camilla,Sommella, Eduardo,Cascioferro, Stella,Salviati, Emanuela,Novi, Sara,Tecce, Mario Felice,Amodio, Giuseppina,Iraci, Nunzio,Cirrincione, Girolamo,Campiglia, Pietro,Diana, Patrizia,Bertamino, Alessia,Parrino, Barbara,Ostacolo, Carmine
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- PIM KINASE INHIBITOR COMPOSITIONS AND USES THEREOF
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This disclosure relates to compounds and compositions useful as inhibitors of PIM kinases. Also provided are methods of synthesis and methods of use of PIM inhibitors in treating individuals suffering from cancerous malignancies.
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Paragraph 0270
(2020/11/12)
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- C-3 NOVEL TRITERPENONE WITH C-17 REVERSE AMIDE DERIVATIVES AS HIV INHIBITORS
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The present invention relates to C-3 novel triterpenone with C-17 reverse amide compounds of Formula (I); and pharmaceutically acceptable salts thereof, wherein ring Formula (II), R1, R2, R3, R4, R5, R6, R7, 'n' and 'm' are as defined in Formula (I). The invention also relates to C-3 novel triterpenone with C-17 reverse amide derivatives, related compounds, and pharmaceutical compositions useful for the therapeutic treatment of viral diseases and particularly HIV mediated diseases.
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Page/Page column 63; 64
(2018/03/06)
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- Novel indanone derivatives as MAO B/H3R dual-targeting ligands for treatment of Parkinson's disease
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The design of multi-targeting ligands was developed in the last decades as an innovative therapeutic concept for Parkinson's disease (PD) and other neurodegenerative disorders. As the monoamine oxidase B (MAO B) and the histamine H3 receptor (H3R) are promising targets for dopaminergic regulation, we synthetized dual-targeting ligands (DTLs) as non-dopaminergic receptor approach for the treatment of PD. Three series of compounds were developed by attaching the H3R pharmacophore to indanone-related MAO B motifs, leading to development of MAO B/H3R DTLs. Among synthesized indanone DTLs, compounds bearing the 2-benzylidene-1-indanone core structure showed MAO B preferring inhibition capabilities along with nanomolar hH3R affinity. Substitution of C5 and C6 position of the 2-benzylidene-1-indanones with lipophilic substituents revealed three promising candidates exhibiting inhibitory potencies for MAO B with IC50 values ranging from 1931 nM to 276 nM and high affinities at hH3R (Ki 50 = 276 nM, hH3R Ki = 6.5 nM) showed highest preference for MAO B over MAO A (SI > 36). Interestingly, IC50 determinations after preincubation of enzyme and DTLs revealed also nanomolar MAO B potency for 3e (MAO B IC50 = 232 nM), a structural isomer of 3f, and 3d (MAO B IC50 = 541 nM), suggesting time-dependent inhibition modes. Reversibility of inhibition for all three compounds were confirmed by dilution studies in excess of substrate. Thus, indanone-substituted derivatives are promising lead structures for the design of MAO B/hH3R DTLs as novel therapeutic approach of PD therapy.
- Affini, Anna,Hagenow, Stefanie,Zivkovic, Aleksandra,Marco-Contelles, Jose,Stark, Holger
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p. 487 - 497
(2018/02/28)
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- Highly Water-Soluble Cyclopentadienyl and Indenyl Molybdenum(II) Complexes - Second Generation of Molybdenum-Based Cytotoxic Agents
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A series of the cyclopentadienyl and indenyl molybdenum compounds bearing alkylammonium functions [(η5-Cp′)Mo(CO)2(N,NL)][BF4]2 were synthesized and characterized by analytical and spectroscopic methods. The structures of [{η5-C5H4CH2CH2NH(CH2)5}Mo(CO)2(4,7-Ph2-phen)][BF4]2 (4,7-Ph2-phen = 4,7-diphenyl-1,10-phenanthroline) and [(η5-C9H6CH2CH2NHMe2)Mo(CO)2(phen)][BF4]2 (phen = 1,10-phenanthroline) were determined by X-ray crystallography. All of the synthesized compounds exhibit high activity against the human leukemia cell lines MOLT-4 and HL-60. They are approximately one order of magnitude more active than cisplatin. This study has proven that the modification of the outer coordination sphere of molybdenum complexes has a strong impact on their activity and may be successfully used for the design of new highly cytotoxic active species. A series of highly cytotoxic molybdenum(II) complexes are synthesized, and their activity against MOLT-4 and HL-60 leukemia cells is established.
- Mr?zek, Ond?ej,?ebestová, Lucie,Vinklárek, Jaromír,?ezá?ová, Martina,Eisner, Ale?,R??i?ková, Zdeňka,Honzí?ek, Jan
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p. 519 - 529
(2016/02/16)
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- Isoflavone amide type derivative, preparation method and medical application thereof
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The invention relates to the field of medicinal chemistry, and relates to an isoflavone amide type derivative, a preparation method and a medical application thereof, in particular to an isoflavone amide type derivative with the general formula (I), a preparation method thereof, medicine compositions including the isoflavone amide type derivative and a medical application thereof, especially an application of the isoflavone amide type derivative as a medicine for preventing or curing hyperlipemia, obesity or type II diabetes. The general formula (I) is shown in the description.
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Paragraph 0016; 0080; 0081; 0082
(2016/10/10)
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- Exploring the Anticancer Activity of Functionalized Isoindigos: Synthesis, Drug-like Potential, Mode of Action and Effect on Tumor-Induced Xenografts
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Meisoindigo has been used as an indirubin substitute for the treatment of chronic myeloid leukemia (CML) for several years. In view of its poor solubility and erratic absorption, several investigations have focused on developing analogues with more desirable physicochemical profiles. Here, we investigated the structure-activity relationship (SAR) of meisoindigo with respect to its antiproliferative activity on leukemic K562 cells and found that appending a phenalkyl side chain onto the lactam NH resulted in analogues that retained good activity. Furthermore, analogues in which the phenyl ring was substituted with a basic heterocycle were significantly more soluble than meisoindigo while retaining acceptable antiproliferative profiles. The most promising analogue (E)-1-(2-(4-methylpiperazin-1-yl)ethyl)-[3,3′-biindolinylidene]-2,2′-dione (5-4) is more potent than meisoindigo across a panel of malignant cells, with at least 40 times greater solubility than meisoindigo, little or no tendency to aggregate in solution and capable of significantly extending the lifespans of animals with K562 induced xenografts. Mechanistically, it induced apoptotic cell death and disrupted the progression of K562 cells from the G1 to G2 phase. Taken together, our findings highlighted the feasibility of addressing the physicochemical deficits of the isoindigo scaffold by systematic modifications which was achieved without overt loss of growth inhibitory activity.
- Wee, Xi Kai,Yang, Tianming,Go, Mei Lin
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experimental part
p. 777 - 791
(2012/07/17)
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- Bulk gold-catalyzed reactions of diazoalkanes with amines and O2 to give enamines
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Bulk gold powder, consisting of approximately 5-50 μm particles, catalyzes reactions of diazoalkanes E(H)C=N2, where E is CO 2Et or PhC(O), with amines R1R2NH and O 2 to give enamine products (R1R2N)(E)C=CH(E) in 58-94% yield. The reactions are proposed to occur by initial formation of surface-bound (E)(H)C: carbene groups that are attacked by nucleophilic amines. The enamine products are very different than those obtained in reactions catalyzed by homogeneous transition metal complexes. These reactions of diazoalkanes, amines, and O2 represent a new type of bulk gold-catalyzed reaction.
- Zhou, Yibo,Angelici, Robert J.,Keith Woo
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body text
p. 8 - 15
(2010/11/24)
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- A study of 2-piperidino-1-ethanol and its derivatives as antimicrobial additives to oils
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Some derivatives of 1-hydroxy-2-pyperidinoethane were studied as antimicrobial additives to lubricant oils.
- Gamzaeva,Mamedova, P. Sh.,Allakhverdieva,Velieva, G. Kh.,Akhundova,Allakhverdiev
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experimental part
p. 1577 - 1581
(2011/06/20)
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- NOVEL COMPOUNDS OF PROLINE AND MORPHOLINE DERIVATIVES
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The present invention relates to compounds with the formulas (I), (II), and (III), or a pharmaceutically acceptable salt thereof: wherein T is a (4 to 10)-membered heterocyclyl selected from the group consisting of and wherein R1. R2 and R3 are as defined in the specification. The invention also relates to pharmaceutical compositions comprising the compounds of formulas (I), (II), and (III) and methods of treating a condition that is mediated by the modulation of the 11-β-hsd-1 enzyme, the method comprising administering to a mammal an effective amount of a compound of formulas (I), (II), and (III).
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Page/Page column 60
(2008/06/13)
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- Benzopyran-containing compounds and prodrug forms thereof
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Certain benzopyran antiestrogens are disclosed for treating estrogen sensitive diseases such as breast cancer. Prodrug forms provide ease of manufacturing, good shelf life, and bioavailibility.
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- Regioselective alkylation process for preparing substituted benzo[b]thiophenes
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The present invention provides processes for the regioselective alkylation of benzothiophenes.
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- Benzopyran-containing compounds and method for their use
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Certain benzopyran antiestrogens are disclosed for treating estrogen sensitive diseases such as breast cancer. Prodrug forms provide ease of manufacturing, good shelf life, and bioavailability, and preferred stereoisomers are shown to be more effective than racemic mixtures.
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- Sulphonamide derivatives
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The present invention relates to the potentiation of glutamate receptor function using certain sulphonamide derivatives. It also relates to novel sulphonamide derivatives, to processes for their preparation and to pharmaceutical compositions containing them.
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- Synthesis of novel succinamide derivatives having the 5,11-dihydro-6h- pyrido[2,3-b][1,4]benzodiazepin-6-one skeleton as potent and selective M2 muscarinic receptor antagonists. I
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A series of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one derivatives containing the succinamide skeleton has been synthesized and evaluated for M1, M2 and M3 muscarinic receptor binding affinities (in vitro) and M2 and M3 muscarinic receptor antagonistic activities (in vivo). Some of them showed higher and more selective binding affinities for M2 muscarinic receptors than that of AF-DX 116. Among them, 11-[3-[N-[2-(N- benzyl-N-methylamino)ethyl]-N-ethylearbamoyl]propionyl]-5,11-dihydro-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one (68) was found to be the most potent and selective M2 muscarinic receptor antagonist in vitro. This compound also strongly inhibited the oxotremorine-induced bradycardia after intravenous administration and showed 130-fold selectivity for M2 muscarinic receptors over M3 muscarinic receptors in vivo.
- Watanabe, Toshihiro,Kinoyama, Isao,Kakefuda, Akio,Okazaki, Toshio,Takizawa, Kenji,Hirano, Seiko,Shibata, Hiroshi,Yanagisawa, Isao
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p. 996 - 1007
(2007/10/03)
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- Introduction of Pharmacorphoric Groups into Polycyclis Systems. Part 3. Amine Derivatives of Adamantane and Diaza-adamantane
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Methods for introducing various pharmacophoric amine-containing substituents into the adamantane system have been investigated.These include β- and α-aminoalkyloxyimino, β-aminoalkylidine, β-hydroxyethylamino, and β-phenylethylamino.Aminoalkoxyimines were prepared by alkylation of the anion of adamantanone oxime with the corresponding aminoalkyl chloride, and a 2-aminoethylidene derivative was prepared by Witting reaction of 2-dimethylaminoethyltriphenylphosphonium bromide with adamantanone.The reaction of 6-hydroxy-7-methyl-6-phenyladamantane-2,4-dione with aqueous sodium cyanide has been shown to be both regio- and stereo-selective, only the C-2 carbonyl group reacting from the most hindered direction.This is possibly due to stabilisation of the cyanohydrin by hydrogen bonding between the hydroxy and C-4 carbonyl groups.When trimethyl cyanide was used in place of sodium cyanide, the reaction remained regioselective but, in the absence of hydrogen bond stabilisation, the stereoselectivity was lost and two trimethylsilyloxy cyanides were isolated, epimeric at C-2.The stereochemistry of one epimer has been determined by X-ray crystallography, details of which are reported here.Hydrogenation of the trimethylsilyloxy cyanides then gave the corresponding β-hydroxyamine, isolated as the hydrochloride.Finally 5,7-diphenyl-1,3-diaza-adamantan-6-one was prepared by a literature method and converted, with difficulty, into the oxime which was reduced by RedAl to the corresponding amine.
- Hickmott, Peter W.,Wood, Simon,Murray-Rust, Peter
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p. 2033 - 2038
(2007/10/02)
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- Method of manufacturing ketones
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The invention relates to a method for the manufacture of ketones which comprises oxidizing an n-olefin in the presence of a catalyst containing palladium, copper, a halogen, and at least one of specific tertiary amines.
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