- Discovery of phthalazino[1,2-b]-quinazolinone derivatives as multi-target HDAC inhibitors for the treatment of hepatocellular carcinoma via activating the p53 signal pathway
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In view of histone deacetylases (HDACs) as a promising target for cancer therapy, a series of phthalazino[1,2-b]-quinazolinone units were hybrided with ortho-aminoanilide or hydroxamic acid to serve as multi-target HDAC inhibitors for the treatment of solid tumors. Among the target compounds, 8h possessed nano-molar IC50 values toward the tested cancer cells and HDAC subtypes, which was more potent than the HDAC inhibitor SAHA (vorinostat). Mechanism study revealed that compound 8h could suppress the HepG2 cell proliferation via prompting the acetylation of histone 3 (H3) and α-tubulin, and activating the p53 signal pathway as designed. In addition, compound 8h exhibited much stronger in vivo antitumor efficacy than SAHA in the HepG2 xenograft tumor model with negligible toxicity. As a novel multi-target HDAC inhibitor, compound 8h deserves further development as a potential anticancer agent.
- Liu, Qingqing,Zhang, Bin,Wang, Yuanjiang,Wang, Xinyi,Gou, Shaohua
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- Multi-target anti-tumor small molecules and their derivatives, preparation methods, pharmaceutical compositions and applications
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The present invention discloses a class of multi-target anti-tumor small molecules and derivatives thereof, preparation methods, pharmaceutical compositions and applications. The chemical structure of such small molecules as shown in formula I, the derivative of which relates to a pharmaceutically acceptable salt of the small molecule. This class of small molecules and their derivatives has a highly efficient tumor suppressor effect in vivo and abroad, low toxicity to cells and organisms, no genotoxicity; anti-tumor activity is achieved through multi-target action, with pan-HDAC inhibitory activity, and can also effectively activate the p53 pathway, inhibit topoisomerase activity, can be used to prepare anti-tumor drugs; the preparation method is simple and easy to operate.
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Paragraph 0039-0040; 0044-0046
(2022/01/05)
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- Synthesis, biological screening, in silico study and fingerprint applications of novel 1, 2, 4-triazole derivatives
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A series of novel 1,2,4 triazole derivatives were synthesized by treating 4-bromo-2-(4H-1,2,4-triazole-3-yl)aniline (4) with different substituted benzene sulfonyl chlorides 5(a-f) and benzyl bromides 7(a-e). IR, 1H-NMR, 13C-NMR, and
- Chandramohan, Vivek,Govindaiah, Shivaraja,Khan, Ghouse,Shetty P, Raghurama,Sreenivasa, Swamy
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- Phthalazino[1,2-b]quinazolinones as p53 Activators: Cell Cycle Arrest, Apoptotic Response and Bak-Bcl-xl Complex Reorganization in Bladder Cancer Cells
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p53 inactivation is a clinically defined characteristic for cancer treatment-nonresponsiveness. It is therefore highly desirable to develop anticancer agents by restoring p53 function.1 Herein the synthesized phthalazino[1,2-b]quinazolinones were discovered as p53 activators in bladder cancer cells. 10-Bromo-5-(2-dimethylamino-ethylamino)phthalazino[1,2-b]quinazolin-8-one (5da) was identified as the most promising candidate in view of both its anticancer activity and mechanisms of action. 5da exhibited strong anticancer activity on a broad range of cancer cell lines and significantly reduced tumor growth in xenograft models at doses as low as 6 mg/kg. Furthermore, 5da caused cell cycle arrest at S/G2 phase, induced apoptosis, changed cell size, and led to cell death by increasing the proportion of sub-G1 cells. Molecular mechanism studies suggested that accumulation of phospho-p53 in mitochondria after 5da treatment resulted in conformational activation of Bak, thereby evoking cell apoptosis, finally leading to irreversible cancer cell inhibition. Our present studies furnish new insights into the molecular interactions and anticancer mechanisms of phospho-p53-dependent quinazolinone compound.
- Zhang, Guo-Hai,Yuan, Jing-Mei,Qian, Gang,Gu, Chen-Xi,Wei, Kai,Mo, Dong-Liang,Qin, Jiang-Ke,Peng, Yan,Zhou, Zu-Ping,Pan, Cheng-Xue,Su, Gui-Fa
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p. 6853 - 6866
(2017/09/07)
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- The use of biochemical and biophysical tools for triage of high-throughput screening hits - aa case study with escherichia coli phosphopantetheine adenylyltransferase
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High-throughput screening is utilized by pharmaceutical researchers and, increasingly, academic investigators to identify agents that act upon enzymes, receptors, and cellular processes. Screening hits include molecules that specifically bind the target and a greater number of non-specific compounds. It is necessary to 'triage' these hits to identify the subset worthy of further exploration. As part of our antibacterial drug discovery effort, we applied a suite of biochemical and biophysical tools to accelerate the triage process. We describe application of these tools to a series of 9-oxo-4,9-dihydropyrazolo[5, 1-b]quinazoline-2-carboxylic acids (PQ) hits from a screen of Escherichia coli phosphopantetheine adenylyltransferase (PPAT). Initial confirmation of specific binding to phosphopantetheine adenylyltransferase was obtained using biochemical and biophysical tools, including a novel orthogonal assay, isothermal titration calorimetry, and saturation transfer difference NMR. To identify the phosphopantetheine adenylyltransferase sub-site bound by these inhibitors, two techniques were utilized: steady-state enzyme kinetics and a novel 19F NMR method in which fluorine-containing fragments that bind the ATP and/or phosphopantetheine sites serve as competitive reporter probes. These data are consistent with PQs binding the ATP sub-site. In addition to identification of a series of PPAT inhibitors, the described hit triage process is broadly applicable to other enzyme targets in which milligram quantities of purified target protein are available.
- Miller, J. Richard,Thanabal, Venkataraman,Melnick, Michael M.,Lall, Manjinder,Donovan, Charles,Sarver, Ronald W.,Lee, Doh-Yeel,Ohren, Jeff,Emerson, Don
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scheme or table
p. 444 - 454
(2011/02/21)
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- REACTIONS OF 2-METHYLPYRAZOLOQUINAZOLIN-9-ONE DERIVATIVES
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The directions of reactions of the titlie compounds (1) with formaldehyde and amines (secondary and primary) and with aromatic aldehydes, have been studied.It has been found that hydrogen atom substitution in position 3 is favorized.As a result of peracet
- Hahn, Witold E.,Osinski, Janusz
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p. 411 - 424
(2007/10/02)
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- The Chemistry of 2-Aminobenzoyl Hydrazides. 1. Effects of Orthoester Substituents on the Mode of Cyclization
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Treatment of substituted 2-aminobenzoyl hydrazides with orthoesters has been found to yield different products depending upon the type of orthoester employed.Equimolar quantities of orthoester and hydrazide yield 3-amino-4(3H)-quinazolinones, whereas utilization of a two-fold excess (or greater) of orthoester yields, in some cases, 3,4-dihydro-5H-1,3,4-benzotriazepin-5-ones as minor products in addition to N-imidate esters as major products.Treatment of hydrazides with trimethyl orthobenzoate yields substituted 5-(2-aminophenyl)-1,3,4-oxadiazoles and 3,4-dihydro-5H-1,3,4-benzotriazepin-5-ones.The steric bulk of the phenyl group in trimethyl orthobenzoate effects the formation of adduct at the β-nitrogen of the hydrazide which cyclized to the oxadiazole and benzotriazepinone products.In the aliphatic orthoester series, the formation of adduct to the aromatic amino group appears to be favored which gives rise to quinazolinone and benzotriazepinone products.
- Leiby, Robert W.
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p. 1825 - 1832
(2007/10/02)
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