457635-26-6Relevant academic research and scientific papers
Structural optimization of non-nucleoside DNA methyltransferase inhibitor as anti-cancer agent
Zhong, Bo,Vatolin, Sergei,Idippily, Nethrie D.,Lama, Rati,Alhadad, Laila A.,Reu, Frederic J.,Su, Bin
, p. 1272 - 1275 (2016/02/23)
Inhibition of DNA methyltransferase 1 (DNMT1) can reverse the malignant behavior of cancer cells by restoring expression of aberrantly silenced genes that are required for differentiation, senescence, and apoptosis. Clinically used DNMT1 inhibitors decitabine and azacitidine inhibit their target by covalent trapping after incorporation into DNA as azacytidine analogs. These nucleoside compounds are prone to rapid enzymatic inactivation in blood, posing challenges to the development of purely epigenetic dosing schedules. Non-nucleoside compounds that suppress expression or function of DNMT1 may overcome this problem. Using a high-throughput PCR-based site specific chromatin condensation assay, we identified a compound that reactivated Cyclin-Dependent Kinase Inhibitor 2A (CDKN2A) in myeloma cells and suppressed expression of DNMT1 from a library of 5120 chemically diverse small molecules. Lead optimization was performed to generate 26 new analogs with lung cancer proliferation and DNMT1 expression as activity readout. Two of the new derivatives showed 2 fold improvement of growth inhibiting potency and also decreased DNMT1 protein levels in lung cancer cells.
The discovery of long-acting saligenin β2 adrenergic receptor agonists incorporating hydantoin or uracil rings
Procopiou, Panayiotis A.,Barrett, Victoria J.,Bevan, Nicola J.,Butchers, Peter R.,Conroy, Richard,Emmons, Amanda,Ford, Alison J.,Jeulin, Séverine,Looker, Brian E.,Lunniss, Gillian E.,Morrison, Valerie S.,Mutch, Peter J.,Perciaccante, Rossana,Ruston, Mark,Smith, Claire E.,Somers, Graham
experimental part, p. 4192 - 4201 (2011/08/22)
A series of novel, potent and selective human β2 adrenoceptor agonists incorporating a hydantoin or a uracil ring on the right-hand side phenyl ring of (R)-salmeterol is presented. Hydantoin 12a had long duration of action in vitro on guinea pi
