133041-91-5Relevant academic research and scientific papers
Synthesis of original thiazoloindolo[3,2-c]quinoline and novel 8-N-substituted-11H-indolo[3,2-c]quinoline derivatives from benzotriazoles. Part I
Beauchard, Anne,Chabane, Hadjila,Sinbandhit, Sourisak,Guenot, Pierre,Thiéry, Valérie,Besson, Thierry
, p. 1895 - 1903 (2006)
Synthesis of novel thiazoloindolo[3,2-c]quinoline and 8-substituted-11H- indolo[3,2-c]quinolines was performed via Graebe-Ullmann thermal cyclization from appropriated N-arylated benzotriazoles. 7H-4,7-Diaza-benzo[de]anthracene, a by-product reaction stru
Selective non-nucleoside inhibitors of human DNA methyltransferases active in cancer including in cancer stem cells
Valente, Sergio,Liu, Yiwei,Schnekenburger, Michael,Zwergel, Clemens,Cosconati, Sandro,Gros, Christina,Tardugno, Maria,Labella, Donatella,Florean, Cristina,Minden, Steven,Hashimoto, Hideharu,Chang, Yanqi,Zhang, Xing,Kirsch, Gilbert,Novellino, Ettore,Arimondo, Paola B.,Miele, Evelina,Ferretti, Elisabetta,Gulino, Alberto,Diederich, Marc,Cheng, Xiaodong,Mai, Antonello
, p. 701 - 713 (2014/03/21)
DNA methyltransferases (DNMTs) are important enzymes involved in epigenetic control of gene expression and represent valuable targets in cancer chemotherapy. A number of nucleoside DNMT inhibitors (DNMTi) have been studied in cancer, including in cancer stem cells, and two of them (azacytidine and decitabine) have been approved for treatment of myelodysplastic syndromes. However, only a few non-nucleoside DNMTi have been identified so far, and even fewer have been validated in cancer. Through a process of hit-to-lead optimization, we report here the discovery of compound 5 as a potent non-nucleoside DNMTi that is also selective toward other AdoMet-dependent protein methyltransferases. Compound 5 was potent at single-digit micromolar concentrations against a panel of cancer cells and was less toxic in peripheral blood mononuclear cells than two other compounds tested. In mouse medulloblastoma stem cells, 5 inhibited cell growth, whereas related compound 2 showed high cell differentiation. To the best of our knowledge, 2 and 5 are the first non-nucleoside DNMTi tested in a cancer stem cell line.
Design, synthesis and biological evaluation of 4-Amino-N-(4-aminophenyl) benzamide analogues of quinoline-based SGI-1027 as inhibitors of DNA methylation
Rilova, Elodie,Erdmann, Alexandre,Gros, Christina,Masson, Veronique,Aussagues, Yannick,Poughon-Cassabois, Valerie,Rajavelu, Arumugam,Jeltsch, Albert,Menon, Yoann,Novosad, Natacha,Gregoire, Jean-Marc,Vispe, Stephane,Schambel, Philippe,Ausseil, Frederic,Sautel, Francois,Arimondo, Paola B.,Cantagrel, Frederic
, p. 590 - 601 (2014/03/21)
Quinoline derivative SGI-1027 (N-(4-(2-amino-6-methylpyrimidin-4-ylamino) phenyl)-4-(quinolin-4-ylamino)benzamide) was first described in 2009 as a potent inhibitor of DNA methyltransferase (DNMT) 1, 3A and 3B. Based on molecular modeling studies, performed using the crystal structure of Haemophilus haemolyticus cytosine-5 DNA methyltransferase (MHhaI C5 DNMT), which suggested that the quinoline and the aminopyridimine moieties of SGI-1027 are important for interaction with the substrates and protein, we designed and synthesized 25 derivatives. Among them, four compounds - namely the derivatives 12, 16, 31 and 32 - exhibited activities comparable to that of the parent compound. Further evaluation revealed that these compounds were more potent against human DNMT3A than against human DNMT1 and induced the re-expression of a reporter gene, controlled by a methylated cytomegalovirus (CMV) promoter, in leukemia KG-1 cells. These compounds possessed cytotoxicity against leukemia KG-1 cells in the micromolar range, comparable with the cytotoxicity of the reference compound, SGI-1027. Structure-activity relationships were elucidated from the results. First, the presence of a methylene or carbonyl group to conjugate the quinoline moiety decreased the activity. Second, the size and nature of the aromatic or heterocycle subsitutents effects inhibition activity: tricyclic moieties, such as acridine, were found to decrease activity, while bicyclic substituents, such as quinoline, were well tolerated. The best combination was found to be a bicyclic substituent on one side of the compound, and a one-ring moiety on the other side. Finally, the orientation of the central amide bond was found to have little effect on the biological activity. This study provides new insights in to the structure-activity relationships of SGI-1027 and its derivative. Ep-(igenet)-ic! Guided by modeling studies, derivatives of the known DNA methyltransferase (DNMT) inhibitor SGI-1027 were designed, synthesized and evaluated. Structure-activity relationships were derived from the results, leading to the identification of derivatives with improved potency and potential for further development.
DNA-Direcred Alkylating Agents. 4. 4-Anilinoquinoline-Based Minor Groove Directed Aniline Mustards
Gravatt, G. Lance,Baguley, Bruce C.,Wilson, William R.,Denny, William A.
, p. 1552 - 1560 (2007/10/02)
A series of 4-anilinoquinoline-linked aniline mustards of widely varying mustard reactivity were prepared and evaluated for their antitumor activity.The compounds were designed as minor groove binding agents, where the aniline mustard ring is itself part of the DNA-binding ligand.While there was a general trend for cytotoxicity to correlate with mustard reactivity, this was much less pronounced than with untargeted mustards.The compounds were much more cytotoxic than the parent diols, and were also at least 10-fold more cytotoxic than the corresponding aniline mustards themselves.Comparative cell line studies suggested that the mechanism of cytotoxicity varied with mustard reactivity.The most reactive mustards cross-linked DNA, while cell killing by the less reactive compounds appeared to be by the formation of bulky monoadducts.The compounds were active but not particularly dose-potent against P388 leukemia in vivo.The modest potency may be related to their poor aqueous solubility, since the more soluble methyl quarternary salts were equally active at much lower doses.
