100981-05-3Relevant articles and documents
Straightforward synthesis of novel substituted 1,3,4-thiadiazole derivatives in choline chloride-based deep eutectic solvent
Shahcheragh, Seyyed Mohammad,Habibi, Azizollah,Khosravi, Sahar
, p. 855 - 859 (2017)
A one-pot, three-component route for the synthesis of novel 1,3,4-thiadiazole derivatives using a ketene S,S-acetal, a carbonyl compound and thiocarbohydrazide is described. The main advantages of this approach are high yields, short reaction times, simple reaction conditions and a green reaction medium. The 1,3,4-thiadiazole core has been substituted with biologically active groups such as arylhydrazones, coumarin, isatin, Meldrum's acid and barbituric acid. Structures of the thiadiazoles were elucidated from spectroscopic data.
Identification of a Potent Phosphoinositide 3-Kinase Pan Inhibitor Displaying a Strategic Carboxylic Acid Group and Development of Its Prodrugs
Pirali, Tracey,Ciraolo, Elisa,Aprile, Silvio,Massarotti, Alberto,Berndt, Alex,Griglio, Alessia,Serafini, Marta,Mercalli, Valentina,Landoni, Clarissa,Campa, Carlo Cosimo,Margaria, Jean Piero,Silva, Rangel L.,Grosa, Giorgio,Sorba, Giovanni,Williams, Roger,Hirsch, Emilio,Tron, Gian Cesare
, p. 1542 - 1554 (2017/09/26)
Activation of the phosphoinositide 3-kinase (PI3K) pathway is a key signaling event in cancer, inflammation, and other proliferative diseases. PI3K inhibitors are already approved for some specific clinical indications, but their systemic on-target toxicity limits their larger use. In particular, whereas toxicity is tolerable in acute treatment of life-threatening diseases, this is less acceptable in chronic conditions. In the past, the strategy to overcome this drawback was to block selected isoforms mainly expressed in leukocytes, but redundancy within the PI3K family members challenges the effectiveness of this approach. On the other hand, decreasing exposure to selected target cells represents a so-far unexplored alternative to circumvent systemic toxicity. In this manuscript, we describe the generation of a library of triazolylquinolones and the development of the first prodrug pan-PI3K inhibitor.
Quinolinone and pyridopyrimidinone inhibitors of DNA-dependent protein kinase
Barbeau, Olivier R.,Cano-Soumillac, Celine,Griffin, Roger J.,Hardcastle, Ian R.,Smith, Graeme C. M.,Richardson, Caroline,Clegg, William,Harrington, Ross W.,Golding, Bernard T.
, p. 2670 - 2677 (2008/03/11)
8-Substituted 2-morpholin-4-yl-quinolin-4-ones and 9-substituted 2-morpholin-4-yl-pyrido[1,2-a]pyrimidin-4-ones with selected aryl and heteroaryl groups as the substituent have been synthesised as potential inhibitors of DNA-dependent protein kinase. A multiple-parallel approach, employing Suzuki cross-coupling methodology, was utilised in the preparation of 8-substituted 2-morpholin-4-yl-quinolin-4-ones. For this purpose 8-bromo-2-morpholin-4-yl- quinolin-4-one was required as an intermediate. This compound was obtained by adapting a literature route in which thermal cyclocondensation of (2-bromoanilino)-morpholin-4-yl-5-methylene-2,2-dimethyl[1,3]dioxane-4,6-dione afforded 8-bromo-2-morpholin-4-yl-quinolin-4-one. A multiple-parallel approach, employing Suzuki cross-coupling methodology, was also utilised to prepare 9-substituted 2-morpholin-4-yl-pyrido[1,2-a]pyrimidin-4-ones using 9-hydroxy-2-morpholin-4-yl-pyrido[1,2-a]pyrimidin-4-one O- trifluoromethanesulfonate as an intermediate. 8-Substituted 2-morpholin-4-yl- quinolin-4-ones and 9-substituted 2-morpholin-4-yl-pyrido[1,2-a]pyrimidin-4-ones were both inhibitors of DNA-dependent protein kinase. When the substituent was dibenzothiophen-4-yl, dibenzofuran-4-yl or biphen-3-yl, IC50 values in the low nanomolar range were observed. Interestingly, the pyridopyrimidinones and quinolinones were essentially equipotent with the corresponding 8-substituted 2-morpholin-4-yl-chromen-4-ones previously reported (I. R. Hardcastle, X. Cockcroft, N. J. Curtin, M. Desage El-Murr, J. J. J. Leahy, M. Stockley, B. T. Golding, L. Rigoreau, C. Richardson, G. C. M. Smith and R. J. Griffin, J. Med. Chem., 2005, 48, 7829-7846). The Royal Society of Chemistry.
