- 8-substituted styryl xanthine derivative and application thereof
-
The invention discloses an 8-substituted styryl xanthine derivative and application thereof, and particularly relates to a novel 8-substituted styryl xanthine derivative and a pharmaceutical composition containing the 8-substituted styryl xanthine derivat
- -
-
Paragraph 0266-0272
(2020/05/01)
-
- Histone deacetylase and proteasome double-target inhibitor, and preparation method and application thereof
-
The invention relates to a protein deacetylase and proteasome double-target inhibitor, and a pharmaceutically acceptable salt, a stereoisomer, a preparation method and an application thereof. The compound is represented by general formula I, the compound has good histone deacetylase resisting activity, proteasome resisting activity and tumor cell proliferation resisting activity, and can be used for preparing medicines for preventing or treating related mammalian diseases caused by abnormal histone deacetylase expression or proteasome abnormality. The invention also relates to a pharmaceuticalapplication of a composition containing the compound with the structure of general formula I.
- -
-
Paragraph 0120-0121
(2020/04/17)
-
- Discovery of peptide boronate derivatives as histone deacetylase and proteasome dual inhibitors for overcoming bortezomib resistance of multiple myeloma
-
While proteasome inhibitors such as bortezomib showed satisfactory clinical benefits in the initial treatment of multiple myeloma (MM), drug resistance and relapse are unavoidable. Recent studies suggested inhibition of histone deacetylases (HDACs) restored sensitivity of bortezomib-resistant MM. Hence, we designed dual inhibitors targeting both HDACs and proteasomes to address the resistance of bortezomib. The most potent inhibitors, ZY-2 and ZY-13 showed excellent inhibition against proteasome and good selectivity against HDACs. In particular, ZY-2 not only exhibited good antiproliferative activities on the MM cell lines RPMI-8226, U266, and KM3 (IC50 values of 6.66, 4.31, and 10.1 nM, respectively) but also showed more potent antiproliferative activities against the bortezomib-resistant MM cell line KM3/BTZ compared with bortezomib (IC50 values of 8.98 vs. 226 nM, P 50 values of 8.98 vs. 98.0 nM, P 0.01).
- Zhou, Yi,Liu, Xiaoting,Xue, Junxin,Liu, Lulu,Liang, Tao,Li, Wen,Yang, Xinying,Hou, Xuben,Fang, Hao
-
p. 4701 - 4715
(2020/06/08)
-
- Bioassay of ferulic acid derivatives as influenza neuraminidase inhibitors
-
Four series of ferulic acid derivatives were designed, synthesized, and evaluated for their neuraminidase (NA) inhibitory activities against influenza virus H1N1 in vitro. The pharmacological results showed that the majority of the target compounds exhibited moderate influenza NA inhibitory activity, which was also better than that of ferulic acid. The two most potent compounds were 1m and 4a with IC50 values of 12.77 ± 0.47 and 12.96 ± 1.34 μg/ml, respectively. On the basis of the biological results, a preliminary structure–activity relationship (SAR) was derived and discussed. Besides, molecular docking was performed to study the possible interactions of compounds 1p, 2d, 3b, and 4a with the active site of NA. It was found that the 4-OH-3-OMe group and the amide group (CON) of ferulic acid amide derivatives were two key pharmacophores for NA inhibitory activity. It is meaningful to further modify the natural product ferulic acid to improve its influenza NA inhibitory activity.
- Cui, Man-Ying,Xiao, Meng-Wu,Xu, Lv-Jie,Chen, Yun,Liu, Ai-Lin,Ye, Jiao,Hu, Ai-Xi
-
-
- HETEROCYCLIC MITOCHONDRIAL ACTIVITY INHIBITORS AND USES THEREOF
-
Heterocyclic compounds of Formula (I) and pharmaceutically acceptable salt thereof are disclosed. The use of such heterocyclic compounds and pharmaceutically acceptable salt thereof for the treatment of cancers, and more particularly cancers sensitive to mitochondrial activity inhibition and increased reactive oxygen species (ROS) levels, is also disclosed. Such cancers include acute myeloid leukemia (AML), preferably AML characterized by certain features, such as high level of expression of one or more Homeobox (HOX)-network genes, high and/or low expression of specific genes, the presence of one or more cytogenetic or molecular risk factors such as intermediate cytogenetic risk, Normal Karyotype (A/K), mutated NPM1, mutated CEBPA, mutated FLT3, mutated DNMT3A, mutated TET2, mutated IDH1, mutated IDH2, mutated RUNX1, mutated WT1, mutated SRSF2, intermediate cytogenetic risk with abnormal karyotype (intern(abnK)), trisomy 8 (+8) and/or abnormal chromosome (5/7), and/or a high leukemic stem cell (LSC) frequency.
- -
-
Page/Page column 131-132
(2019/05/22)
-
- Discovery and anti-inflammatory evaluation of benzothiazepinones (BTZs) as novel non-ATP competitive inhibitors of glycogen synthase kinase-3β (GSK-3β)
-
Glycogen synthase kinase-3β (GSK-3β) has been identified to promote inflammation and its inhibitors have also been proven to treat some inflammatory mediated diseases in animal models. Non-ATP competitive inhibitors inherently have better therapeutical value due to their higher specificity than ATP competitive ones. In this paper, we designed and synthesized a series of new BTZ derivatives as non-ATP competitive GSK-3β inhibitors. Kinetic analysis revealed two typical compounds 6j and 3j showed the different non-ATP competitive mechanism of substrate competition or allosteric modulation to GSK-3β, respectively. As expected, the two compounds showed good specificity in a panel test of 16 protein kinases, even to the closest enzymes, like CDK-1/cyclin B and CK-II. The in vivo results proved that both compounds can greatly attenuate the LPS-induced acute lung injury (ALI) and diminish inflammation response in mice by inhibiting the mRNA expression of IL-1β and IL-6. Western blot analysis demonstrated that they negatively regulated GSK-3β, and the mechanism of the observed beneficial effects of the inhibitors may involve both the increased phosphorylation of the Ser9 residue on GSK-3β and protein expression of Sirtuin 1 (SIRT1). The results support that such novel BTZ compounds have a protective role in LPS-induced ALI, and might be attractive candidates for further development of inflammation pharmacotherapy, which greatly thanks to their inherently high selectivities by the non-ATP competitive mode of action. Finally, we proposed suggesting binding modes by Docking study to well explain the impacts of compounds on the target site.
- Gao, Yang,Zhang, Peng,Cui, Anfeng,Ye, De-Yong,Xiang, Meng,Chu, Yong
-
p. 5479 - 5493
(2018/10/09)
-
- Transition-metal-free C-P bond formation via decarboxylative phosphorylation of cinnamic acids with P(O)H compounds
-
A novel, transition-metal-free phosphorylation of cinnamic acids with P(O)H compounds has been developed via radical-promoted decarboxylation under mild conditions. This method provides simple, efficient, and versatile access to valuable (E)-alkenylphosphine oxides in satisfactory yields with a wide variety of substrates.
- Liu, Lixin,Zhou, Dan,Dong, Jianyu,Zhou, Yongbo,Yin, Shuang-Feng,Han, Li-Biao
-
p. 4190 - 4196
(2018/04/14)
-
- Polystyrene supported palladium nanoparticles catalyzed cinnamic acid synthesis using maleic anhydride as a substitute for acrylic acid
-
Maleic anhydride was explored as a substitute for acrylic acid to synthesize cinnamic acids from aryl halides under heterogeneous palladium catalyzed conditions. The combined role of surface and impregnated catalyst together performed an upright engineering to hold in situ generated molecules on the surface and subsequently facilitate their interaction for the desired product synthesis. Overall, a surface mediated approach for cinnamic acid synthesis from maleic anhydride following a major unexplored pathway through catalyst promoted decarboxylation was critically investigated.
- Thakur, Vandna,Kumar, Sandeep,Das, Pralay
-
p. 3692 - 3697
(2017/09/07)
-
- 4-Biphenylalanine- and 3-Phenyltyrosine-Derived Hydroxamic Acids as Inhibitors of the JumonjiC-Domain-Containing Histone Demethylase KDM4A
-
Overexpression of the histone lysine demethylase KDM4A, which regulates H3K9 and H3K36 methylation states, has been related to the pathology of several human cancers. We found that a previously reported hydroxamate-based histone deacetylase (HDAC) inhibitor (SW55) was also able to weakly inhibit this demethylase with an IC50value of 25.4 μm. Herein we report the synthesis and biochemical evaluations, with two orthogonal in vitro assays, of a series of derivatives of this lead structure. With extensive chemical modifications on the lead structure, also by exploiting the versatility of the radical arylation with aryldiazonium salts, we were able to increase the potency of the derivatives against KDM4A to the low-micromolar range and, more importantly, to obtain demethylase selectivity with respect to HDACs. Cell-permeable derivatives clearly showed a demethylase-inhibition-dependent antiproliferative effect against HL-60 human promyelocytic leukemia cells.
- Morera, Ludovica,Roatsch, Martin,Fürst, Michael C. D.,Hoffmann, Inga,Senger, Johanna,Hau, Mirjam,Franz, Henriette,Schüle, Roland,Heinrich, Markus R.,Jung, Manfred
-
p. 2063 - 2083
(2016/10/22)
-
- Design, synthesis and cytotoxic evaluation of novel imatinib amide derivatives that target Abl kinase
-
Novel imatinib amide derivatives (a1-28, b1-9) were synthesized and evaluated for their biological activities. All compounds were characterized by 1H NMR, MS and elemental analysis. Among all the derivatives, compounds a4, a10, a21, b1 and b2 displayed the most significant ability of inhibiting K562 cell proliferation with the IC50 values of 0.67, 0.66, 0.65, 0.59 and 0.62 μM, respectively, indicating that these compounds were potent inhibitors of Bcr-Abl in leukemic K562 cells, comparable to the reference compound imatinib. Molecular docking study was performed to position compounds a21 and b1 into the active site of Abl to determine the probable binding modes
- Yao, Ri-Sheng,Guan, Qiu-Xiang,Lu, Xiao-Qin,Ruan, Ban-Feng
-
-
- CINNAMIC ACID AMIDE DERIVATIVE
-
The present invention provides a cinnamic acid amide derivative having an excellent analgesic action. The cinnamic acid amide derivative of the present invention is a compound showing excellent analgesic actions to not only a nociceptive pain model animal but also a neuropathic pain model animal, which is very useful as an agent for treating various pain diseases showing acute or chronic pains or neuropathic pains.
- -
-
Paragraph 0086; 0096
(2015/11/24)
-
- A biocompatible alkene hydrogenation merges organic synthesis with microbial metabolism
-
Organic chemists and metabolic engineers use orthogonal technologies to construct essential small molecules such as pharmaceuticals and commodity chemicals. While chemists have leveraged the unique capabilities of biological catalysts for small-molecule production, metabolic engineers have not likewise integrated reactions from organic synthesis with the metabolism of living organisms. Reported herein is a method for alkene hydrogenation which utilizes a palladium catalyst and hydrogen gas generated directly by a living microorganism. This biocompatible transformation, which requires both catalyst and microbe, and can be used on a preparative scale, represents a new strategy for chemical synthesis that combines organic chemistry and metabolic engineering. Reduction to practice: A hydrogenation reaction has been developed that employs hydrogen generated in situ by a microorganism and a biocompatible palladium catalyst to reduce alkenes on a synthetically useful scale. This type of transformation, which directly combines tools from organic chemistry with the metabolism of a living organism for small-molecule production, represents a new strategy for chemical synthesis.
- Sirasani, Gopal,Tong, Liuchuan,Balskus, Emily P.
-
supporting information
p. 7785 - 7788
(2014/08/05)
-
- Design, synthesis and biological evaluation of nitro oxide donating N-hydroxycinnamamide derivatives as histone deacetylase inhibitors
-
Novel nitro oxide (NO)-donating N-hydroxycinnamamide derivatives 12a-j were designed and synthesized by coupling the carboxyl group of N-hydroxycinnamamides with phenylsulfonylfuroxan through various diols or alkylol amines, and their in vitro biological activities were evaluated. It was discovered that most of target compounds showed good histone deacetylases (HDACs) inhibition and anti-tumor activities, particularly for 12j, which had great HDACs inhibitory activities (IC50s=0.15-0.26 μm) and antiproliferative effects (IC50s=3.21-7.12 μm) comparable to suberoylanilide hydroxamic acid (SAHA) (IC50s=0.16-1.41 μm for HDACs, IC50s=3.15-7.45 μm for cancer cell inhibition). Furthermore, compound 12j with strong antitumor activities produced high levels of NO (up to 8.0 μm of nitrites/nitrates) in colon cancer cells, and its antiproliferative activity was nearly half-diminished by hemoglobin (10 μm), an NO scavenger. These results suggest that the strong antiproliferative activity of 12j could be attributed to the additive effects of high levels of NO production and inhibition of HDAC in the cancer cells.
- Tu, Shiliang,Yuan, Hang,Hu, Jie,Zhao, Chengguang,Chai, Rui,Cao, Hongfeng
-
p. 1185 - 1191
(2015/02/19)
-
- COMPOUNDS HAVING PHOTOCHEMICALLY REMOVABLE PROTECTING GROUPS BASED ON AN ELECTROCYCLIC REACTION BETWEEN A CHROMOPHORE ATTACHED VIA AN ANILIDE GROUP TO A BENZOTHIOPHENE RING
-
Disclosed herein are compounds having photoremovable protecting groups which are removed after the compounds absorbs light of a given wavelength and undergo an electrocyclic reaction between a chromophore in the compound attached via an anilide to a benzothiophene ring.
- -
-
Paragraph 0045
(2013/09/12)
-
- HISTONE DEACETYLASE INHIBITORS
-
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.
- -
-
Page/Page column 42
(2012/09/21)
-
- NOVEL N-SUBSTITUTED-PYRROLIDINES AS INHIBITORS OF MDM2-P-53 INTERACTIONS
-
There are provided compounds of the formula wherein X, Y, R1, R2, R3, R3, R4, and R5 are as described herein and enantiomers and pharmaceutically acceptable salts and esters thereof which are useful as anticancer agents.
- -
-
-
- Paracyclophanes: Extending the bridges. Synthesis
-
Preparatively satisfactory routes to [3.2]paracyclophane (10), [4.2]paracyclophane (14), [4.3]paracyclophane (19) as well as several derivatives of these compounds - among others the bromides 25, the ester 31, the diesters 40-43 - are described using well-established methods of cyclophane chemistry (ring-closure reactions leading to thiacyclophanes, ring contraction by sulfone pyrolysis). The parent systems and their derivatives are now available in gram quantities allowing a study of their chemical properties. Wiley-VCH Verlag GmbH & Co. KGaA, 2009.
- Pechlivanidis, Zissis,Hopf, Henning,Ernst, Ludger
-
experimental part
p. 223 - 237
(2009/06/21)
-
- NOVEL BIFUNCTIONAL COMPOUNDS WHICH INHIBIT PROTEIN KINASES AND HISTONE DEACETYLASES
-
The present invention relates to a bifunctional compound of formula I or its pharmaceutically acceptable salts or solvates A-L-B (I) wherein A is a histone deacetylase (HDAC) inhibitory moiety, L is a single bond or a linker group and B is a protein kinase inhibitory moiety. The bifunctional compound according to formula (I) is useful for the treatment of malignant and non-malignant neoplasia and diseases related to abnormal cell growth
- -
-
Page/Page column 84
(2009/06/27)
-
- Design of chimeric histone deacetylase- and tyrosine kinase-inhibitors: A series of Imatinib hybrides as potent Inhibitors of wild-type and mutant BCR-ABL, PDGF-Rβ, and histone deacetylases
-
Inhibitors of histone deacetylases are a new class of cancer therapeutics with possibly broad applicability. Combinations of HDAC inhibitors with the kinase inhibitor 1 (Imatinib) in recent studies showed additive and synergistic effects. Here we present a new concept by combining inhibition of protein kinases and HDACs, two independent pharmacological activities, in one synthetic small molecule. In general, the HDAC inhibition profile, the potencies, and the probable binding modes to HDAC1 and HDAC6 were similar as for 6 (SAHA). Inhibition of Abl kinase in biochemical assays was maintained for most compounds, but in general the kinase selectivity profile differed from that of 1 with nearly equipotent inhibition of the wildtype and the Imatinib resistant Abl T315I mutant. A potent cellular inhibition of PDGFR and cytotoxicity toward EOL-1 cells, a model for idiopathic hypereosinophilic syndrome (HES), are restored or enhanced for selected analogues (12b, 14b, and 18b). Cytotoxicity was evaluated by using a broad panel of tumor cell lines, with selected analogues displaying mean IC50 values between 3.6 and 7.1 μM.
- Mahboobi, Siavosh,Dove, Stefan,Sellmer, Andreas,Winkler, Matthias,Eichhorn, Emerich,Pongratz, Herwig,Ciossek, Thomas,Baer, Thomas,Maier, Thomas,Beckers, Thomas
-
experimental part
p. 2265 - 2279
(2009/12/31)
-
- Palladium-catalysed arylation of poly(ethylene glycol) bound acrylate with aryl iodides in water: A liquid-phase synthesis of trans-cinnamic acids
-
An efficient liquid-phase synthesis of trans-cinnamic acids with good yields and high purities on soluble polymer support has been developed by treatment of poly(ethylene glycol) bound acrylate with aryl iodides in the presence of catalytic amounts of palladium acetate and tetra-n-butylammonium bromide in water using potassium carbonate as a base, and subsequent cleavage from the PEG.
- Sheng, Shou-Ri,Luo, Qiu-Yan,Huang, Pei-Gang,Guo, Lei,Wang, Qiu-Ying,Pei, Xue-Liang
-
-
- Silica-supported bidentate arsine palladium(0) complex: A highly active and stereoselective catalyst for arylation of conjugated alkenes
-
A silica-supported bidentate arsine palladium(0) complex has been prepared from 4-oxa-6,7-dichloroheptyltriethoxysilane via immobilization on fumed silica, followed by reacting with potassium diphenylarsenide and palladium chloride, and then the reduction with hydrazine hydrate. The complex has been characterized by X-ray photoelectron spectroscopy and it is a highly active and stereoselective catalyst for arylation of styrene and acrylic acid with aryl halides affording a variety of trans -stilbenes and substituted trans -cinnamic acids in high yields.
- Cai, Mingzhong,Huang, Yizheng,Zhao, Hong,Song, Caisheng
-
-
- Heck arylation of conjugated alkenes catalysed by a silica-supported poly-γ-methylselenopropylsiloxane palladium(0) complex, the first polymeric organoselenium palladium complex
-
A silica-supported poly-γ-methylselenopropylsiloxane palladium(O) complex was prepared from poly-γ-chloropropylsiloxane by treatment with sodium methyl-selenolate, followed by reaction with palladium chloride and then reduction with hydrazine hydrate. The first polymeric organoselenium palladium complex is a highly active and stereoselective catalyst for the arylation of conjugated alkenes.
- Cai, Ming-Zhong,Zhou, Jun,Zhao, Hong,Song, Cai-Sheng
-
-
- Process for the preparation of methyl p-vinylbenzoate and p-vinyl benzoic acid, and their use in latex compositions
-
The present invention describes a process for the direct preparation of methyl p-vinylbenzoate from methyl p-formylbenzoate using ketene in the presence of potassium acetate. The chief products obtained from the process are about a five to two ratio of methyl p-vinylbenzoate to p-carbomethoxycinnamic acid. The latter may be thermally decarboxylated, especially in the presence of copper powder, to produce additional quantities of methyl p-vinylbenzoate. Methyl p-vinylbenzoate may further undergo hydrolysis to form p-vinyl benzoic acid. Both methyl p-vinyl benzoate and p-vinyl benzoic acid may be polymerized with ethylenically unsaturated monomers to form useful latex compositions of the present invention.
- -
-
-
- Silica-supported poly-γ-mercaptopropylsiloxane palladium(0) complex: A highly active and stereoselective catalyst for arylation of styrene and acrylic acid
-
A silica-supported poly-γ-mercaptopropylsiloxane palladium(0) complex was prepared from poly-γ-mercaptopropylsiloxane and palladium chloride in acetone, followed by reduction with hydrazine in ethanol. The complex is a highly active and stereoselective catalyst for arylation of styrene and acrylic acid affording a variety of trans-stilbenes and substituted trans- cinnamic acids in high yields.
- Cai, Ming-Zhong,Song, Cai-Sheng,Huang, Xian
-
p. 521 - 523
(2007/10/03)
-
- Syntheses of (rac)3-Substituted 4-Methoxycarbonyl-1,3-thiazolidine-2-thiones via Rearrangement of a Substituted Group from exo-S to N in (rac)2-Substituted Thio-4-methoxycarbonyl-Δ2-1,3-thiazolines
-
Based on the previously obtained structural information, (rac)3-substituted 4-carboxy-1,3-thiazolidine-2-thiones 10 were designed as new aldose reductase inhibitors which might be helpful in treating the chronic complications of diabetes.After several trials to find efficient reaction conditions for preparation of the precursors 15 of compounds 10, a catalytic thermal rearrangement reaction of 14 proved to be practically available.Thus, various 3-substituted 4-methoxycarbonyl-1,3-thiazolidine-2-thiones 15a and 15d-t were readily synthesized by heating tha corresponding 2-substituted thio-Δ2-1,3-thiazolines 14a and 14d-t at 120 deg C in the presence of 0.1 mol eq of the corresponding halides 13a and 13d-t without any organic solvent (Sykes conditions).A plausible reaction pathway for the catalytic thermal rearrangement reaction of 14a or 14d-t is presented.Keywords - aldose reductase inhibitor; (rac)2-substituted thio-4-methoxycarbonyl-Δ2-1,3-thiazoline; (rac)3-substituted 4-methoxycarbonyl-1,3-thiazolidine-2-thione; Sykes-type reaction; rearrangement; stepwise cationic reaction; concerted bimolecular transition state
- Nagao, Yoshimitsu,Inoue, Keiko,Yamaki, Masae,Takagi, Shuzo,Fujita, Eiichi
-
p. 495 - 508
(2007/10/02)
-