- Selective HDAC inhibitors with potent oral activity against leukemia and colorectal cancer: Design, structure-activity relationship and anti-tumor activity study
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Previously, we reported the discovery of a series of N-hydroxycinnamamide-based HDAC inhibitors, among which compound 11y exhibited high HDAC1/3 selectivity. In this current study, structural derivatization of 11y led to a new series of benzamide based HDAC inhibitors. Most of the compounds exhibited high HDACs inhibitory potency. Compound 11a (with 4-methoxybenzoyl as N-substituent in the cap and 4-(aminomethyl) benzoyl as the linker group) exhibited selectivity against HDAC1 to some extent, and showed potent antiproliferative activity against several tumor cell lines. In?vivo studies revealed that compound 11a displayed potent oral antitumor activity in both hematological tumor cell U937 xenograft model and solid tumor cell HCT116 xenograft model with no obvious toxicity. Further modification of benzamide 3, 11a and 19 afforded new thienyl and phenyl compounds (50a, 50b, 63a, 63b and 63c) with dramatic HDAC1 and HDAC2 dual selectivity, and the fluorine containing compound 56, with moderate HDAC3 selectivity.
- Li, Xiaoyang,Zhang, Yingjie,Jiang, Yuqi,Wu, Jingde,Inks, Elizabeth S.,Chou, C. James,Gao, Shuai,Hou, Jinning,Ding, Qinge,Li, Jingyao,Wang, Xue,Huang, Yongxue,Xu, Wenfang
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p. 185 - 206
(2017/04/21)
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- Discovery of multi-target anticancer agents based on HDAC inhibitor MS-275 and 5-FU
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Histone deacetylases (HDACs) inhibitors have multiple effects targeting the cancer cells and have become one of the promising cancer therapeutics with possibly broad applicability. Combination of HDAC inhibitors with the cytotoxic fluorouracil (5-FU) show
- Jiang, Yuqi,Li, Xiaoguang,Li, Xiaoyang,Hou, Jinning,Ding, Yongzheng,Zhang, Jian,Xu, Wenfang,Zhang, Yingjie
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- PYRAZOLONE DERIVATIVE HAVING CYCLIC SIDE CHAIN
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PROBLEM TO BE SOLVED: To provide a compound that has excellent inhibitory action on ATPase activity of TIP48/TIP49 complex and is therefore useful for the treatment of tumor, or a pharmacologically acceptable salt thereof. SOLUTION: The present invention provides a compound having a structure represented by general formula (I), its pharmacologically acceptable salt, or a pharmaceutical composition comprising the compound (where R1, R2, R3, R4, R5, R6, R7, W, and Z are as defined in the specifications). SELECTED DRAWING: None COPYRIGHT: (C)2016,JPOandINPIT
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Paragraph 0289; 0290
(2016/10/08)
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- THERAPEUTIC COMPOUNDS AND COMPOSITIONS
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Compounds of general formula (I) and compositions comprising compounds of general formula I that modulate pyruvate kinase are described herein. Also described herein are methods of using the compounds that modulate pyruvate kinase in the treatment of diseases.
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Page/Page column 115
(2014/09/29)
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- THERAPEUTIC COMPOUNDS AND COMPOSITIONS
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Compounds of general formula I: and compositions comprising compounds of general formula I that modulate pyruvate kinase are described herein. Also described herein are methods of using the compounds that modulate pyruvate kinase in the treatment of diseases.
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Paragraph 0401
(2014/09/30)
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- THERAPEUTIC COMPOUNDS AND COMPOSITIONS
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Compounds of general formula (I) and compositions comprising compounds of general formula (I) that modulate pyruvate kinase are described herein. Also described herein are methods of using the compounds that modulate pyruvate kinase in the treatment of diseases.
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Page/Page column 129; 130
(2014/09/29)
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- HETEROCYCLIC ANTIVIRAL COMPOUNDS
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Compounds having the formula I wherein A, R1, R2, R3, R4a, R4b, R4c, R5, R6, R7a, R7b, Ar1, Rc, Rd, Re/sup
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- Tyrosine bioconjugation through aqueous ene-type reactions: A click-like reaction for tyrosine
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(Figure Presented) A new and versatile class of cyclic diazodicarboxamides that reacts efficiently and selectively with phenols and the phenolic side chain of tyrosine through an ene-like reaction is reported. This mild aqueous tyrosine ligation reaction works over a broad pH range and expands the repertoire of aqueous chemistries available for small molecule, peptide, and protein modification. The tyrosine ligation reactions are shown to be compatible with the labeling of native enzymes and antibodies in a buffered aqueous solution. This reaction provides a novel synthetic approach to bispecific antibodies. We believe this reaction will find broad utility in peptide and protein chemistry and in the chemistry of phenol-containing compounds.
- Ban, Hitoshi,Gavrilyuk, Julia,Barbas III, Carlos F.
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supporting information; experimental part
p. 1523 - 1525
(2010/04/03)
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- Quantitation of folates and their catabolites in blood plasma, erythrocytes, and urine by stable isotope dilution assays
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New stable isotope dilution assays were developed for the simultaneous quantitation of the folates 5-methyltetrahydrofolic acid, 5-formyltetrahydrofolic acid, tetrahydrofolic acid, 10-formylfolic acid, and folic acid as well as for their catabolites para-aminobenzoylglutamate (pABG) and acetyl-para-aminobenzoylglutamate (ApABG) in clinical samples. The methods were based on cleanup by strong anion exchange followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) detection. Deuterated analogues of the folates and [13C5]-labeled isotopologues of the catabolites were applied as the internal standards in stable isotope dilution assays. Extraction in 4-morpholineethanesulfonic acid (MES) buffer at pH 5.0 ensured the optimum stability of folates and, in combination with solid-phase extraction (SPE) based on strong anion exchange, resulted in higher recoveries compared with other combinations of extraction buffers and SPE. The method was sensitive enough to detect pABG in plasma generally and unmetabolized folic acid in the plasma of a volunteer after oral dosage of an aqueous folic acid solution. The sum of folate catabolites increased by a factor of 2 in the urine of the latter volunteer, compared with that resulting when only water was dosed.
- Moench, Sabine,Netzel, Michael,Netzel, Gabriele,Rychlik, Michael
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scheme or table
p. 150 - 160
(2011/12/02)
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- Design of antiangiogenic hypoxic cell radiosensitizers: 2-Nitroimidazoles containing a 2-aminomethylene-4-cyclopentene-1,3-dione moiety
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We designed chiral 2-nitroimidazole derivatives containing a 2-aminomethylene-4-cyclopentene-1,3-dione moiety as antiangiogenic hypoxic cell radiosensitizers. Based on results of molecular orbital calculations, the 2-aminomethylene-4-cyclopentene-1,3-dion
- Uto, Yoshihiro,Nagasawa, Hideko,Jin, Cheng-Zhe,Nakayama, Shinichi,Tanaka, Ayako,Kiyoi, Saori,Nakashima, Hitomi,Shimamura, Mariko,Inayama, Seiichi,Fujiwara, Tomoya,Takeuchi, Yoshio,Uehara, Yoshimasa,Kirk, Kenneth L.,Nakata, Eiji,Hori, Hitoshi
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p. 6042 - 6053
(2008/12/21)
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- The synthesis of folic acid, multiply labelled with stable isotopes, for bio-availability studies in human nutrition
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Two different methods for the synthesis of folic acid, which are suitable for the incorporation of compounds multiply labelled with stable isotopes, are described. The first method is based on the use of a novel reductive amination to link 2-acetyIamino-4-hydroxy-6-formylpteridine withp-aminobenzoyl-L-glutamic acid. The second method is based on the penultimate formation of an amide bond between Ar-2-acetyl-Ar-10-trifluoroacetyIpteroic acid and dimethyl L-glutamate. Both methods have been used to transform [13C6]aniline into folic acid, labelled with [13C6] in the p-aminobenzoate moiety, and [3,3,4,4-2H4]-L-glutamic acid into folic acid, labelled with [2H4] in the glutamate moiety. Doubly labelled [13C6,2H 4]-p-aminobenzoyl-L-glutamate has also been prepared by the former method.
- Maunder, Peter,Finglas, Paul M.,Mallet, Anthony I.,Mellon, Fred A.,Aaqib Razzaque,Ridge, Brian,Vahteristo, Liisa,Witthoeft, Cornelia
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p. 1311 - 1323
(2007/10/03)
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- Synthesis and structure-activity relationships of 2- pyrazinylcarboxamidobenzoates and β-ionylideneacetamidobenzoates with retinoidal activity
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The structure-activity relationships of two series of novel retinoids (2-pyrazinylcarboxamidobenzoates and β-ionylideneacetamidobenzoates) have been investigated by evaluating their ability to induce differentiation in both human promyelocytic leukemia (H
- Jones, Paul,Villeneuve, Gérald B.,Fei, Chengpei,DeMarte, Josie,Haggarty, Allison J.,Nwe, Khin Than,Martin, Deborah A.,Lebuis, Anne-Marie,Finkelstein, Joshua M.,Gour-Salin, Barbara J.,Chan, Tak Hang,Leyland-Jones, Brian R.
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p. 3062 - 3077
(2007/10/03)
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- Substituted benzene derivatives useful as neuraminidase inhibitors
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A compound of the Formula (I): STR1 or pharmaceutically-suitable salts or prodrug forms thereof, wherein: n is 0-1; m is 0; p is 0-1; R1 is --CO2 H; R2 is selected from the group consisting of H, --OH, and --NH2 ; R3 is H; R4 is --C(O)NHR8 ; R5 is --NHC(R6)NH2 R6 is selected from the group consisting of =NH, =NOH, =NCN, =O, and =S; and R8 is selected from the group consisting of C1 -C4 linear or branched alkyl substituted with 0-3 halogens on each carbon.
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