- Design and Synthesis of Novel Reactive Oxygen Species Inducers for the Treatment of Pancreatic Ductal Adenocarcinoma
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Altering redox homeostasis provides distinctive therapeutic opportunities for the treatment of pancreatic cancer. Quinazolinediones (QDs) are novel redox modulators that we previously showed to induce potent growth inhibition in pancreatic ductal adenocarcinoma (PDAC) cell lines. Our lead optimization campaign yielded QD325 as the most potent redox modulator candidate inducing substantial reactive oxygen species (ROS) in PDAC cells. Nascent RNA sequencing following treatments with the QD compounds revealed induction of stress responses in nucleus, endoplasmic reticulum, and mitochondria of pancreatic cancer cells. Furthermore, the QD compounds induced Nrf2-mediated oxidative stress and unfolded protein responses as demonstrated by dose-dependent increases in RNA synthesis of representative genes such as NQO1, HMOX1, DDIT3, and HSPA5. At higher concentrations, the QDs blocked mitochondrial function by inhibiting mtDNA transcription and downregulating the mtDNA-encoded OXPHOS enzymes. Importantly, treatments with QD325 were well tolerated in vivo and significantly delayed tumor growth in mice. Our study supports the development of QD325 as a new therapeutic in the treatment of PDAC.
- Kuang, Yuting,Sechi, Mario,Nurra, Salvatore,Ljungman, Mats,Neamati, Nouri
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- A Novel Redox Modulator Induces a GPX4-Mediated Cell Death That Is Dependent on Iron and Reactive Oxygen Species
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Redox modulators have been developed as an attractive approach to treat cancer. Herein, we report the synthesis, identification, and biological evaluation of a quinazolinedione reactive oxygen species (ROS) inducer, QD394, with significant cytotoxicity in pancreatic cancer cells. QD394 shows a transcriptomic profile remarkably similar to napabucasin, a cancer stemness inhibitor. Both small molecules inhibit STAT3 phosphorylation, increase cellular ROS, and decrease the GSH/GSSG ratio. Moreover, QD394 causes an iron- and ROS-dependent, GPX4 mediated cell death, suggesting ferroptosis as a major mechanism. Importantly, QD394 decreases the expression of LRPPRC and PNPT1, two proteins involved in mitochondrial RNA catabolic processes and both negatively correlated with the overall survival of pancreatic cancer patients. Pharmacokinetics-guided lead optimization resulted in the derivative QD394-Me, which showed improved plasma stability and reduced toxicity in mice compared to QD394. Overall, QD394 and QD394-Me represent novel ROS-inducing drug-like compounds warranting further development for the treatment of pancreatic cancer.
- Hu, Shuai,Sechi, Mario,Singh, Pankaj Kumar,Dai, Lipeng,Mccann, Sean,Sun, Duxin,Ljungman, Mats,Neamati, Nouri
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- Synthesis and cytotoxicity of analogues of the antibiotic BE 10988 inhibitors of DNA topoisomerase II
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Indolequinone derivatives of the antitumour antibiotic BE 10988 were synthesized and evaluated for their cytotoxicity and action mechanism. The quinone system is essential to biological activity and the thiazole ring plays a major role in the poisoning of
- Catrycke, Marc-Olivier,Houssin, Raymond,Henichart, Jean-Pierre,Pfeiffer, Bruno,Renard, Pierre,Dassonneville, Laurent,Bailly, Christian
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- Discovery of 5-(pyridin-3-yl)-1H-indole-4,7-diones as indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors
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Early studies demonstrated that over expression of indoleamine 2,3-dioxygenase (IDO1) in tumor microenvironment results in tumor immune escape. Herein, in order to simplify the structure of two kinds of IDO1 inhibitors from marine alkaloid, Exiguamine A and Tsitsikammamines, we designed, synthesized a series of 1H-indole-4,7-dione derivatives and evaluated their inhibitory activity in IDO1 enzyme and in IFN-γ stimulated Hela cells in vitro. The structure-activity relationship demonstrated that 5-(pyridin-3-yl)-1H-indole-4,7-dione is a promising scaffold for IDO1 inhibitors and most compounds with this core showed moderate inhibition potency at micromole level. Our further enzyme kinetics experiments reveal that these new developed compounds might act as reversible competitive inhibitors of IDO1.
- Kong, Kai-min,Liu, Bing-zhi,Meng, Guang-rong,Zhang, Jia-wei,Zhang, Qian
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- Targeted Nanoparticles for the Delivery of Novel Bioactive Molecules to Pancreatic Cancer Cells
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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with poor prognosis and limited therapeutic options. Therefore, there is an urgent need to identify new, safe, and targeted therapeutics for effective treatment of late as well as early stage disease. Plectin-1 (Plec-1) was recently identified as specific biomarker for detecting PDAC at an early stage. We envisioned that multivalent attachment of nanocarriers incorporating certain drugs to Plec-1-derived peptide would increase specific binding affinity and impart high specificity for PDAC cells. Previously, we discovered a novel class of compounds (e.g., quinazolinediones, QDs) that exert their cytotoxic effects by modulating ROS-mediated cell signaling. Herein, we prepared novel QD242-encapsulated polymeric nanoparticles (NPs) functionalized with a peptide to selectively bind to Plec-1. Similarly, we prepared QD-based NPs densely decorated with an isatoic anhydride derivative. Furthermore, we evaluated their impact on ligand binding and antiproliferative activity against PDAC cells. The targeted NPs were more potent than the nontargeted constructs in PDAC cells warranting further development.
- Sanna, Vanna,Nurra, Salvatore,Pala, Nicolino,Marceddu, Salvatore,Pathania, Divya,Neamati, Nouri,Sechi, Mario
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- Re-examination of the synthesis of 3,5-dimethoxy-2-nitrobenzaldehyde
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An efficient and reproducible synthetic method is proposed for the preparation of 2-nitro-3,6-dimethoxybenzaldehyde.
- Del Mar Blanco,Avendano,Cabezas,Menendez
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Read Online
- Triazolo Quinazoline Dione Derivatives
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The present invention relates to a triazolo quinazolinedione derivative. A novel synthesized triazolo quinazolinedione derivative inhibits proliferation of cancer cells, and an anticancer activity is shown in a living organism. Accordingly, a compound of the present invention can be useful in the cancer treatment field. The compound has a chemical structure of chemical formula 1.COPYRIGHT KIPO 2017
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Paragraph 0082-0087
(2018/04/06)
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- Novel indole derivative and medicine containing the same (by machine translation)
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[A] formation of Amyloid fibrils can be compounds, including therapeutic or prophylactic agent for neurodegenerative disease Amyloid fibrils formation inhibitor compound and of. (I) or its pharmaceutically acceptable compound represented by the formula [a] or a salt or solvate thereof includes the, Amyloid fibrils formation inhibitor. [R1 And R2 Each independently is H, an alkyl group, a cyano group or the like; R3 And R4 Each independently is H, or an alkyl group; R3 And R4 The, joint may form a ring; Ar1 And Ar2 The substituted or unsubstituted heteroaryl group are independently substituted/unsubstituted aryl groups /; X and Y are each independently a single bond, - (=O) - C etc., Z is O or CH2 ; N is an integer of 1 - 3][Drawing] no (by machine translation)
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Paragraph 0152; 0155
(2018/06/30)
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- SMALL MOLECULE INDUCERS OF REACTIVE OXYGEN SPECIES AND INHIBITORS OF MITOCHONDRIAL ACTIVITY
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This invention is in the field of medicinal chemistry. In particular, the invention relates to a new class of small-molecules having a quinazolinedione structure which function as reactive oxygen species (ROS) inducers and inhibitors of mitochondrial activity within cancer cells (e.g., pancreatic cancer cells), and their use as therapeutics for the treatment of cancer (e.g., pancreatic cancer) and other diseases.
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Page/Page column 58; 61
(2017/09/27)
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- Synthesis and antiproliferative activity of new cytotoxic tri- and tetraazabenzo[3,2-a]fluorene-5,6-dione derivatives
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A new series of substituted tri-/tetraazabenzo[3,2-a]fluorene-5,6-diones and their corresponding oxime derivatives have been synthesized and spectroscopically characterized. The antiproliferative activities of all compounds were evaluated on at least thre
- Leepasert, Theerachart,Shahabi, Manochehr,Shanab, Karem,Schirmer, Eva,Holzer, Wolfgang,Spreitzer, Helmut,Aicher, Babette,Mueller, Gilbert,Guenther, Eckhard
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p. 5264 - 5266
(2013/09/23)
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- Nucleophilic substitution of nitro groups by [18F]fluoride in methoxy-substituted ortho-nitrobenzaldehydes-A systematic study
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As model reactions for the introduction of [18F]fluorine into aromatic amino acids, the replacement of NO2 by [18F]fluoride ion in mono- to tetra-methoxy-substituted ortho-nitrobenzaldehydes was systematically investigated. Unexpectedly, the highly methoxylated precursors 2,3,4-trimethoxy-6-nitrobenzaldehyde and 2,3,4,5-tetramethoxy-6-nitrobenzaldehyde showed high maximum radiochemical yields (82% and 48% respectively). When the electrophilicity of the leaving group substituted carbon atom is expressed by its 13C NMR chemical shift a good correlation with the reaction rate at the beginning of the reaction (first min) was found (R2 = 0.89), whereas the maximum radiochemical yields correlated much poorer with this electrophilicity parameter. This may be caused by side reactions becoming influencial in the further reaction course. As possible side reactions the demethylation of methoxy groups and intramolecular redox reactions could be detected by HPLC/MS.
- Shen, Bin,L?ffler, Dirk,Reischl, Gerald,Machulla, Hans-Jürgen,Zeller, Klaus-Peter
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experimental part
p. 216 - 224
(2009/07/25)
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- Synthesis and adrenolytic activity of 1-(1H-indol-4-yloxy)-3-(2-(2-methoxy phenoxy)ethylamino)propan-2-ol analogs and its enantiomers. Part 2
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The synthesis of (2RS)-1-(5-methoxy-1H-indol-4-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)propan-2-ol and (2RS)-1-(7-methoxy-1H-indol-4-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)propan-2-ol and its enantiomers, analogs of 1-(1H-indol-4-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)propan-2-ol ((RS)-9) is described. Compounds were tested for electrographic, antiarrhythmic, hypotensive and spasmolytic activities as well as for α1-, α2- and β1-adrenoceptors binding affinities. The antagonist potency of the new compounds was compared with carvedilol and (RS)-9.
- Groszek, Grazyna,Nowak-Krol, Agnieszka,Wdowik, Tomasz,Swierczynski, Dariusz,Bednarski, Marek,Otto, Monika,Walczak, Maria,Filipek, Barbara
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experimental part
p. 5103 - 5111
(2010/02/28)
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- Efficient synthesis of novel six-member ring-fused quinoline derivatives via the Friedlaender reaction
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Novel quinolines fused with a six-member ring 5a-j were prepared in high yields (75-95%) via the Friedlaender reaction of dimethoxy-substituted o-aminobenzaldehydes of 3a or 3b with cyclic ketones 4, respectively. The structures of 5aj were determined by IR, 1H NMR, MS, and elemental analysis.
- Yang, Dingqiao,Guo, Wei,Cai, Yuepeng,Jiang, Lasheng,Jiang, Kailing,Wu, Xiaobing
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p. 229 - 233
(2008/09/19)
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- Synthesis of hipposudoric and norhipposudoric acids: The pigments responsible for the color reaction of the red sweat of Hippopotamus amphibius
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Highly unstable pigments, hipposudoric acid and norhipposudoric acid, isolated from the red sweat of hippopotamus were synthesized using the Pschorr reaction for the construction of the fluorene nucleus as the key step and the careful oxidation in the las
- Saikawa, Yoko,Moriya, Kai,Hashimoto, Kimiko,Nakata, Masaya
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p. 2535 - 2538
(2007/10/03)
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- Synthesis and cytotoxic activity of 2-acyl-1H-indole-4,7-diones on human cancer cell lines
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Synthesis and cytotoxic activity of a series of 2-acyl-1H-indole-4,7-diones on human cancer cell lines are described. Due to close structural relationship to 2-acylindoles, potent inhibitors of tubulin polymerization, the mode of action of these novel com
- Mahboobi, Siavosh,Sellmer, Andreas,Eichhorn, Emerich,Beckers, Thomas,Fiebig, Heinz-Herbert,Kelter, Gerhard
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- 6-Arylamino-7-chloro-quinazoline-5,8-diones as novel cytotoxic and DNA topoisomerase inhibitory agents
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A series of 6-arylamino-7-chloro-quinazoline-5,8-diones were prepared and evaluated for their in vitro cytotoxicity in cultured human cancer cell lines A549 (lung cancer), Col2 (colon cancer), and SNU-638 (stomach cancer). The preliminary structure-activity relationship has been described for providing further development of potent antitumor agents. To further investigate the cytotoxic mechanism, the effects of test compounds on DNA topoisomerase I and II activities have been assessed.
- Park, Hyen Joo,Kim, Young-Shin,Kim, Jin Sung,Lee, Eun-Jin,Yi, You-Jin,Hwang, Hye Jin,Suh, Myung-Eun,Ryu, Chung-Kyu,Lee, Sang Kook
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p. 3385 - 3388
(2007/10/03)
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- Tandem radical cyclisation and translocation approaches to biologically important mitomycin ring systems
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New free-radical cyclisation and translocation approaches to the tricyclic mitomycin ring system have been developed. These convergent approaches involve either a tandem 5-endo/5-exo radical cyclisation or alternatively, a 1,6-hydrogen-atom transfer follo
- Allan, Gillian M.,Parsons, Andrew F.,Pons, Jean-Fran?ois
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p. 1431 - 1434
(2007/10/03)
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- Studies on quinones. Part 36. Synthesis and trypanocidal activity of 2-alkoxycarbonylbenzo[b]thiophene-4,7-quinones
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A series of 2-alkoxycarbonylbenzo[b]thiophene-4,7-quinones (11-15), prepared from the corresponding acid 5, were tested in vitro against trypomastigote form of Trypanosome cruzi. The influence of the lypophilia and oxidant capacity upon the trypanocidal a
- Pessoa-Mahana, Carlos D.,Valderrama, Jaime. A.,Olmos, Maria G.,Espinoza, Omar A.,Pessoa-Mahana, Hernan,Rojas de Arias, Antonieta,Nakayama, Hector,Torres, Susana,Miret, Jorge
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p. 135 - 140
(2007/10/03)
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- Synthesis of novel pentacyclic pyrrolothiazolobenzoquinolinones, analogs of natural marine alkaloids
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Multistep synthesis (12 steps) of new pentacyclic compounds, which are structurally very close to natural marine alkaloids, was performed via a Diels-Alder reaction between 4-methylene-5-(bromomethylene)-4,5-dihydrothiazole and a protected dioxotryptamine
- Bénéteau, Valérie,Besson, Thierry
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p. 2673 - 2676
(2007/10/03)
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- 5,8-Dimethoxyharmalan: Actions at 5-HT(2A) serotonin receptors
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Certain β-carbolines bind at 5-HT(2A) and 5-HT(2C) serotonin receptors. In an attempt to determine if these agents bind in a manner that more likely resembles the binding of N,N-dimethyltryptamine (DMT) or 1-(2,5- dimethoxyphenyl)-2-aminopropane (2,5-DMA)
- Hong,Dukat,Teitler,Egan,Dupre,Herrick-Davis,Glennon
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p. 374 - 388
(2007/10/03)
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- Nitration of electron-rich aromatic compounds by cerium ammonium nitrate coated on silica
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Treatment of electron-rich aromatic derivatives with cerium (IV) ammonium nitrate coated on silica (CANSio2) affords nitro aromatic compounds. The scope and the limitation of this reaction are discussed.
- Grenier, Jean-Luc,Catteau, Jean-Pierre,Cotelle, Philippe
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p. 1201 - 1208
(2007/10/03)
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- Incorporation of Quinoline-5,8-quinone Moiety into Polyaza Cavities
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Silica gel supported nitric acid treatment of 2,5-dimethoxybenzaldehyde followed by reduction with iron powder provides 3,6-dimethoxy-2-aminobenzaldehyde.Friedlaender condensation of this species with a variety of ketones and diketones leads to 5,8-dimethoxyquinoline derivatives which may be oxidized by ceric ammonium nitrate (CAN) and pyridine-2,6-dicarboxylic acid N-oxide (PDANO) to the corresponding quinones.The quinone functionality can be incorporated into larger cavities by a selective stepwise Friedlaender approach and the CAN/PDANO oxidation appears to work preferentially for 5,8-dimethoxyquinoline.
- Thummel, Randolph P.,Chirayil, Sara,Hery, Christophe,Lim, Jean-Luc,Wang, Tie-Lin
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p. 1666 - 1671
(2007/10/02)
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- Deprotection of benzaldehyde diacetates by ceric ammonium nitrate coated on silica
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Benzaldehyde diacetates were selectively converted to the corresponding benzaldehydes using Ceric Ammonium Nitrate (CAN) coated on silica in dichloromethane.
- Cotelle, Philippe,Catteau, Jean-Pierre
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p. 3855 - 3858
(2007/10/02)
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- Selective synthesis of 2,5-dimethoxy-4-nitrobenzaldehyde
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A selective preparation of 2,5-dimethoxy-4-nitrobenzaldehyde is proposed in a procedure involving the transformation of the aldehyde group to a diacetoxymethyl group.
- Cotelle,Catteau
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p. 2071 - 2076
(2007/10/02)
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- NITRIC ACID ON SILICA GEL: A USEFUL NITRATING REAGENT FOR ACTIVATED AROMATIC COMPOUNDS
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Phenols and arylmethyl ethers are rapidly mononitrated by nitric acid adsorbed in silica gel at room temperature in high yields.
- Tapia, Ricardo,Torres, Glenda,Valderrama, Jaime A.
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p. 681 - 688
(2007/10/02)
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