2887-61-8Relevant articles and documents
THIOSEMICARBAZONES INHIBITORS OF LYSOPHOSPHATIDIC ACID ACYLTRANSFERASE AND USES THEREOF
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Page/Page column 16, (2015/11/17)
Lysophosphatidic acid acyltransferase-beta (LPAAT-β) catalyzes the production of phosphatidic acid (PA) from lysophosphatidic acid (LPA). The lipid cofactor PA contributes to the activation of c-Raf, BRAF, mTOR and PKC-ζ. LPAAT-β expression is a prognostic factor in gynecologic malignancies and is being investigated as a therapeutic target in a variety of tumor types. A class of thiosemicarbazones was identified as inhibitors of LPAAT-β from a screen of a library of small molecules. A focused library of thiosemicarbazones derivatives was prepared and led to the development of compounds which potently inhibit LPAAT-β and inhibit the growth of MiaPaCa2 human pancreatic cancer cells.
Structure-activity relationships of novel salicylaldehyde isonicotinoyl hydrazone (SIH) analogs: Iron chelation, anti-oxidant and cytotoxic properties
Potuckova, Eliska,Hruskova, Katerina,Bures, Jan,Kovarikova, Petra,Spirkova, Iva A.,Pravdikova, Katerina,Kolbabova, Lucie,Hergeselova, Tereza,Haskova, Pavlna,Jansova, Hana,Machacek, Miloslav,Jirkovska, Anna,Richardson, Vera,Lane, Darius J. R.,Kalinowski, Danuta S.,Richardson, Des R.,Vavrova, Katerina,Simunek, Tomas
, (2015/02/19)
Salicylaldehyde isonicotinoyl hydrazone (SIH) is a lipophilic, tridentate iron chelator with marked anti-oxidant and modest cytotoxic activity against neoplastic cells. However, it has poor stability in an aqueous environment due to the rapid hydrolysis of its hydrazone bond. In this study, we synthesized a series of new SIH analogs (based on previously described aromatic ketones with improved hydrolytic stability). Their structure-activity relationships were assessed with respect to their stability in plasma, iron chelation efficacy, redox effects and cytotoxic activity against MCF-7 breast adenocarcinoma cells. Furthermore, studies assessed the cytotoxicity of these chelators and their ability to afford protection against hydrogen peroxide-induced oxidative injury in H9c2 cardiomyoblasts. The ligands with a reduced hydrazone bond, or the presence of bulky alkyl substituents near the hydrazone bond, showed severely limited biological activity. The introduction of a bromine substituent increased ligand-induced cytotoxicity to both cancer cells and H9c2 cardiomyoblasts. A similar effect was observed when the phenolic ring was exchanged with pyridine (i.e., changing the ligating site from O, N, O to N, N, O), which led to pro-oxidative effects. In contrast, compounds with long, flexible alkyl chains adjacent to the hydrazone bond exhibited specific cytotoxic effects against MCF-7 breast adenocarcinoma cells and low toxicity against H9c2 cardiomyoblasts. Hence, this study highlights important structure-activity relationships and provides insight into the further development of aroylhydrazone iron chelators with more potent and selective anti-neoplastic effects.
Intermolecular C-O addition of carboxylic acids to arynes: Synthesis of o-hydroxyaryl ketones, xanthones, 4-chromanones, and flavones
Dubrovskiy, Anton V.,Larock, Richard C.
, p. 2789 - 2798 (2013/03/29)
An efficient and simple route to biologically and pharmaceutically important o-hydroxyaryl ketones, xanthones, 4-chromanones, and flavones has been developed utilizing readily available carboxylic acids and commercially available o-(trimethylsilyl)aryl tr
