- Synthesis and Evaluation of 2-Alkylthio-4-(N-substituted sulfonamide)pyrimidine Hydroxamic Acids as Anti-myeloma Agents
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A series of pyrimidine hydroxamic acids with a sulfide substituent at the second position and a sulfonamide substituent at the fourth position have been synthesized and evaluated for their activity against human myeloma cell line RPMI 8226. Several compounds exhibited significant anti-cancer potency. It was found that representative compound 6a selectively killed cancerous but not normal cells. Moreover, compound 6a was effective in causing apoptosis in RPMI 8226 cells and exhibited promising HDAC-inhibitory activities.
- Xiang, Jinbao,Leung, Crystal,Zhang, Zhuoqi,Hu, Cassie,Geng, Chao,Liu, Lili,Yi, Lang,Li, Zhiwei,Berenson, James,Bai, Xu
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Read Online
- Design, Synthesis, and Structure-Activity relationships of Evodiamine-Based topoisomerase (Top)/Histone deacetylase (HDAC) dual inhibitors
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On the basis of synergistic effect between topoisomerase (Top) and histone deacetylase (HDAC) inhibitors, a series of novel evodiamine-based Top/HDAC dual inhibitors were designed and synthesized. Systematic structure?activity relationship (SAR) studies led to the discovery of compounds 29b and 45b, which simultaneously inhibited Top and HDAC and exhibited potent antitumor activities against the HCT116 cell line. Compounds 29b and 45b efficiently induced apoptosis with G2 cell cycle arrest and significantly inhibited cellular HDACs in HCT116 cells with good in vitro metabolic stabilities. Collectively, this work provides valuable SAR information and lead compounds for evodiamine-based Top/HDAC dual inhibitors.
- Dong, Guoqiang,Liang, Huixin,Liu, Dan,Meng, Xiangguo,Sheng, Chunquan,Wu, Shanchao,Zhu, Fugui
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supporting information
(2022/03/16)
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- Bicyclic Diazepinones as Dual Ligands of the α2δ-1 Subunit of Voltage-Gated Calcium Channels and the Norepinephrine Transporter
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The synthesis and pharmacological activity of a new series of bicyclic diazepinones with dual activity toward the α2δ-1 subunit of voltage-gated calcium channels (Cavα2δ-1) and the norepinephrine transporter (NET) are reported. Exploration of the positions amenable for substitution on a nonaminoacidic Cavα2δ-1 scaffold allowed the identification of favorable positions for the attachment of NET pharmacophores. Among the patterns explored, attachment of the 2-ethylamino-9-methyl-6-phenyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]diazepin-5-one framework to the meta-position of the phenyl ring of the 3-methylamino-1-phenylpropoxy and 3-methylamino-1-thiophenylpropoxy moieties provided dual compounds with excellent NET functionality. Alternative bicyclic frameworks were also explored, and some lead molecules were identified, which showed a balanced dual profile and exhibited good ADMET properties.
- Díaz, José Luis,Cuevas, Félix,Pazos, Gonzalo,álvarez-Bercedo, Paula,Oliva, Ana I.,Sarmentero, M. ángeles,Font, Daniel,Jiménez-Aquino, Agustín,Morón, María,Port, Adriana,Pascual, Rosalía,Dordal, Albert,Portillo-Salido, Enrique,Reinoso, Raquel F.,Vela, José Miguel,Almansa, Carmen
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p. 2167 - 2185
(2021/03/09)
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- Pyrimidine hydroxamicacid derivative and preparation method and application thereof
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The invention provides a pyrimidine hydroxamicacid derivativeshown as a general formula (I) and a preparation method and application thereof. The compound and its pharmaceutically acceptable salt can regulate an HDAC signal transduction pathway, increase the acetylated histone content in cells and selectively kill myeloma cells but have no obvious toxicity to normal human peripheral blood mononuclear cells. Therefore, the compound is expected to be developed into a safe anticancer drug.
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Paragraph 0026; 0030; 0070; 0071
(2017/08/25)
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- PROCESS FOR THE SEPARATION OF ENANTIOMERS OF PIPERAZINE DERIVATIVES
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The invention relates to a process for preparing either enantiomer of a compound of formula (I), wherein X, Y and n have the meaning given in claim 1, with high enantiomeric excess (e.e.), by chiral resolution in the presence of a non-racemic, chiral acid.
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Page/Page column 51; 52
(2017/09/21)
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- ACID ADDITION SALTS OF PIPERAZINE DERIVATIVES
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The invention relates to acid addition salts of piperazine derivatives, as well as solid forms, such as polymorphic forms, thereof, which are useful as pharmaceutical ingredients and in particular as glycosidase inhibitors.
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Page/Page column 87
(2017/09/09)
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- SUBSTITUTED BICYCLIC HETEROARYL COMPOUNDS AS RXR AGONISTS
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The present invention relates to certain substituted bicyclic compounds that are agonists of RXR and which are therefore useful in the treatment of certain disorders that can be prevented or treated by activation of this receptor. In addition the invention relates to the compounds, methods for their preparation, pharmaceutical compositions containing the compounds and the uses of these compounds in the treatment of certain disorders.
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Paragraph 0386
(2016/12/01)
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- GLYCOSIDASE INHIBITORS
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Compounds of formula (I) wherein A, R, W, Q, n and m have the meaning according to the claims can be employed, inter alia, for the treatment of tauopathies and Alzheimer's disease.
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Page/Page column 155
(2016/03/22)
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- DERIVATIVES OF 1-PHENYL-2-PYRIDINYL ALKYL ALCOHOLS AS PHOSPHODIESTERASE INHIBITORS
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The invention relates to inhibitors of the phosphodiesterase 4 (PDE4) enzyme. More particularly, the invention relates to compounds that are derivatives of 1-phenyl-2-pyridinyl alkyl alcohols, methods of preparing such compounds, compositions containing them and therapeutic use thereof.
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Page/Page column 275; 276
(2013/04/13)
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- DERIVATIVES OF 1-PHENYL-2-PYRIDINYL ALKYL ALCOHOLS AS PHOSPHODIESTERASE INHIBITORS
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The invention relates to inhibitors of the phosphodiesterase 4 (PDE4) enzyme. More particularly, the invention relates to compounds that are derivatives of 1-phenyl-2-pyridinyl alkyl alcohols, methods of preparing such compounds, compositions containing them and therapeutic use thereof.
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Paragraph 1022; 1023
(2013/04/10)
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- HISTONE DEACETYLASE INHIBITORS
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Provided herein are isoform selective histone deacetylase inhibitors of the formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, metabolites, prodrugs, solvates, pharmaceutically acceptable salts and compositions thereof. These compounds are isoform selective inhibitors of HDACs and are useful as a therapeutic or ameliorating agent for diseases that are involved in cellular growth such as cancer, malignant tumors, autoimmune diseases, skin diseases, fungal infections, protozoal infections, HIV, inflammation and CNS disorders.
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Page/Page column 44
(2012/09/21)
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- Discovery of 2-(6-{[(6-Fluoroquinolin-2-yl)methyl]amino}bicyclo[3.1.0]hex- 3-yl)- N -hydroxypyrimidine-5-carboxamide (CHR-3996), a class i selective orally active histone deacetylase inhibitor
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A novel series of HDAC inhibitors demonstrating class I subtype selectivity and good oral bioavailability is described. The compounds are potent enzyme inhibitors (IC50 values less than 100 nM), and improved activity in cell proliferation assays was achieved by modulation of polar surface area (PSA) through the introduction of novel linking groups. Employing oral pharmacokinetic studies in mice, comparing drug levels in spleen to plasma, we selected compounds that were tested for efficacy in human tumor xenograft studies based on their potential to distribute into tumor. One compound, 21r (CHR-3996), showed good oral activity in these models, including dose-related activity in a LoVo xenograft. In addition 21r showed good activity in combination with other anticancer agents in in vitro studies. On the basis of these results, 21r was nominated for clinical development.
- Moffat, David,Patel, Sanjay,Day, Francesca,Belfield, Andrew,Donald, Alastair,Rowlands, Martin,Wibawa, Judata,Brotherton, Deborah,Stimson, Lindsay,Clark, Vanessa,Owen, Jo,Bawden, Lindsay,Box, Gary,Bone, Elisabeth,Mortenson, Paul,Hardcastle, Anthea,Van Meurs, Sandra,Eccles, Suzanne,Raynaud, Florence,Aherne, Wynne
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experimental part
p. 8663 - 8678
(2011/03/19)
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- SUBSTITUTED NICOTINAMIDE COMPOUNDS
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The present invention relates to a novel class of substituted nicotinamides. These compounds can inhibit histone deacetylase and are suitable for use in selectively inducing terminal differentiation, and arresting cell growth and/or apoptosis of neoplasti
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Page/Page column 33
(2009/05/29)
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- Inhibitors of Histone Deacetylase
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The invention relates to the inhibition of histone deacetylase. The invention provides compounds and methods for inhibiting histone deacetylase enzymatic activity. The invention also provides compositions and methods for treating cell proliferative diseas
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Page/Page column 27-28
(2008/12/07)
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- HYDROXAMATES AS INHIBITORS OF HISTONE DEACETYLASE
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Compounds of formula (I), and salts, N-oxides, hydrates and solvates thereof are histone deacetylase inhibitors and are useful in the treatment of cell proliferative diseases, including cancers: wherein Q, V and W independently represent -N= or -C=; B is
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Page/Page column 35
(2008/12/05)
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- BENZAMIDE DERIVATIVES AS INHIBITORS OF HISTONE DEACETYLASE
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The invention relates to the inhibition of histone deacetylase. The invention provides compounds which are derivatives of benzamide and suitable in methods for inhibiting histone deacetylase enzymatic activity. The invention also provides compositions and methods for treating cell proliferative diseases and conditions .
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Page/Page column 105
(2008/06/13)
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- SUBSTITUTED NICOTINAMIDE COMPOUNDS
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The present invention relates to a novel class of substituted nicotinamides.. These compounds can inhibit histone deacetylase and are suitable for use in selectively inducing terminal differentiation, and arresting cell growth and/or apoptosis of neoplast
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Page/Page column 63-65
(2010/11/27)
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- HISTONE DEACETYLASE INHIBITORS
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Compounds of formula: (I), and salts, N-oxides, hydrates and solvates thereof are histone deacetylase inhibitors and are useful in the treatment of cell proliferative diseases, including cancers: (I) wherein Q, V and W independently represent -N= or -C=;
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Page/Page column 17; 26-27
(2010/11/25)
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- An efficient synthesis of α-carboline-3-carboxylic acid, ethyl ester (α-CCE)
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The use of the Intramolecular Inverse Electron Demand Diels-Alder reaction between an acetylenic dienophile and a pyrimidine diene component is described in the synthesis of α-CCE.
- Forbes,Johnson,Thompson
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p. 715 - 723
(2007/10/02)
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