7520-95-8Relevant articles and documents
Novel cyanothiouracil and cyanothiocytosine derivatives as concentration-dependent selective inhibitors of U87MG glioblastomas: Adenosine receptor binding and potent PDE4 inhibition
Sahin, Zafer,Biltekin, Sevde Nur,Yurttas, Leyla,Berk, Barkin,?zhan, Ya?mur,Sipahi, Hande,Gao, Zhan-Guo,Jacobson, Kenneth A.,Demirayak, ?eref
, (2021/01/12)
Thiouracil and thiocytosine are important heterocyclic pharmacophores having pharmacological diversity. Antitumor and antiviral activity is commonly associated with thiouracil and thiocytosine derivatives, which are well known fragments for adenosine receptor affinity with many associated pharmacological properties. In this respect, 33 novel compounds have been synthesized in two groups: 24 thiouracil derivatives (4a-x) and 9 thiocytosine derivatives (5a-i). Antitumor activity of all the compounds was determined in the U87 MG glioblastoma cell line. Compound 5e showed an anti-proliferative IC50 of 1.56 μM, which is slightly higher activity than cisplatin (1.67 μM). The 11 most active compounds showed no signficant binding to adenosine A1, A2A or A2B receptors at 1 μM. Brain tumors express high amounts of phosphodiesterases. Compounds were tested for PDE4 inhibition, and 5e and 5f showed the best potency (5e: 3.42 μM; 5f: 0.97 μM). Remakably, those compounds were also the most active against U87MG. However, the compounds lacked a cytotoxic effect on the HEK293 healthy cell line, which encourages further investigation.
Dependence on the Pyrimidine Biosynthetic Enzyme DHODH Is a Synthetic Lethal Vulnerability in Mutant KRAS-Driven Cancers
Koundinya, Malvika,Sudhalter, Judith,Courjaud, Albane,Lionne, Bruno,Touyer, Gaetan,Bonnet, Luc,Menguy, Isabelle,Schreiber, Isabelle,Perrault, Christelle,Vougier, Stephanie,Benhamou, Brigitte,Zhang, Bailin,He, Timothy,Gao, Qiang,Gee, Patricia,Simard, Daniel,Castaldi, M. Paola,Tomlinson, Ronald,Reiling, Stephan,Barrague, Matthieu,Newcombe, Richard,Cao, Hui,Wang, Yanjun,Sun, Fangxian,Murtie, Joshua,Munson, Mark,Yang, Eric,Harper, David,Bouaboula, Monsif,Pollard, Jack,Grepin, Claudine,Garcia-Echeverria, Carlos,Cheng, Hong,Adrian, Francisco,Winter, Christopher,Licht, Stuart,Cornella-Taracido, Ivan,Arrebola, Rosalia,Morris, Aaron
, p. 705 - 11,717 (2018/06/21)
Activating KRAS mutations are major oncogenic drivers in multiple tumor types. Synthetic lethal screens have previously been used to identify targets critical for the survival of KRAS mutant cells, but their application to drug discovery has proven challenging, possibly due in part to a failure of monolayer cultures to model tumor biology. Here, we report the results of a high-throughput synthetic lethal screen for small molecules that selectively inhibit the growth of KRAS mutant cell lines in soft agar. Chemoproteomic profiling identifies the target of the most KRAS-selective chemical series as dihydroorotate dehydrogenase (DHODH). DHODH inhibition is shown to perturb multiple metabolic pathways. In vivo preclinical studies demonstrate strong antitumor activity upon DHODH inhibition in a pancreatic tumor xenograft model. Koundinya et al. show that inhibitors of the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase selectively inhibit the growth of KRAS mutant cell lines. Differential sensitivity of the mutant lines correlates with differential effects of the inhibitors on primary energy metabolism and glutamine levels, and the inhibitors synergize with some clinically used anticancer agents.
Fused Heterocycles: Synthesis and Antitubercular Activity of Novel 6-Substituted-2-(4-methyl-2-substituted phenylthiazol-5-yl)H-imidazo[1,2-a]pyridine
Abhale, Yogita K.,Deshmukh, Keshav K.,Sasane, Amit V.,Chavan, Abhijit P.,Mhaske, Pravin C.
, p. 229 - 233 (2015/03/18)
(Chemical Equation Presented) A series of 6-substituted-2-(4-methyl-2-substituted phenylthiazol-5-yl)H-imidazo[1,2-a]pyridine derivatives 4a-4l is described. The antitubercular activity of the synthesized compounds was determined against Mycobacterium smegmatis MC2 155 strain. From the activity result, it was found that the phenyl or 4-fluorophenyl group at 2 position of thiazole nucleus and bromo substituent at 6 position of imidazo[1,2-a]pyridine showed good antitubercular activity.
