703-59-3Relevant articles and documents
Discovery and Optimization of a Selective Ligand for the Switch/Sucrose Nonfermenting-Related Bromodomains of Polybromo Protein-1 by the Use of Virtual Screening and Hydration Analysis
Myrianthopoulos, Vassilios,Gaboriaud-Kolar, Nicolas,Tallant, Cynthia,Hall, Michelle-Lynn,Grigoriou, Stylianos,Brownlee, Peter Moore,Fedorov, Oleg,Rogers, Catherine,Heidenreich, David,Wanior, Marek,Drosos, Nikolaos,Mexia, Nikitia,Savitsky, Pavel,Bagratuni, Tina,Kastritis, Efstathios,Terpos, Evangelos,Filippakopoulos, Panagis,Müller, Susanne,Skaltsounis, Alexios-Leandros,Downs, Jessica Ann,Knapp, Stefan,Mikros, Emmanuel
, p. 8787 - 8803 (2016)
Bromodomains (BRDs) are epigenetic interaction domains currently recognized as emerging drug targets for development of anticancer or anti-inflammatory agents. In this study, development of a selective ligand of the fifth BRD of polybromo protein-1 (PB1(5)) related to switch/sucrose nonfermenting (SWI/SNF) chromatin remodeling complexes is presented. A compound collection was evaluated by consensus virtual screening and a hit was identified. The biophysical study of protein-ligand interactions was performed using X-ray crystallography and isothermal titration calorimetry. Collective data supported the hypothesis that affinity improvement could be achieved by enhancing interactions of the complex with the solvent. The derived SAR along with free energy calculations and a consensus hydration analysis using WaterMap and SZmap algorithms guided rational design of a set of novel analogues. The most potent analogue demonstrated high affinity of 3.3 μM and an excellent selectivity profile, thus comprising a promising lead for the development of chemical probes targeting PB1(5).
Unexpected formal [4 + 2]-cycloaddition of chalcone imines and homophthalic anhydrides: preparation of dihydropyridin-2(1H)-ones
Guranova, Natalia,Golubev, Pavel,Bakulina, Olga,Dar'in, Dmitry,Kantin, Grigory,Krasavin, Mikhail
supporting information, p. 3829 - 3833 (2021/05/14)
A series of medicinally important dihydropyridin-2(1H)-ones have been preparedviaa novel [4 + 2]-formal cycloaddition reaction of chalcone imines and homophthalic anhydrides, which is a rare example of lactam construction from an imine acting as a four-atom building block. In contrast to previous studies on the reactivity of homophthalic anhydrides towards similar substrates,N-tosyl chalcone imines, we found the possibility of switching chemoselectivity by changing substituents at the nitrogen atom, which leads to the formation of heterocycles instead of the expected carbocycles. This reaction is very similar in appearance to the classic 1,2-addition of cyclic anhydrides to imines, often referred to as the Castagnoli-Cushman reaction, but differs in mechanistic details (representing a 1,4-reaction of imine). The developed atom-economical, stereoselective and catalyst- and chromatography-free protocol provided facile access to 28 structurally diverse heterocyclic products (in up to 88% yield) including synthetically challenging annelated tricyclic and previously unreported pentaaryl-substituted dihydropyridin-2(1H)-ones.
Highly Enantio- and Diastereoselective Catalytic Asymmetric Tamura Cycloaddition Reactions
Collar, Aarón Gutiérrez,Trujillo, Cristina,Connon, Stephen J.
supporting information, p. 7270 - 7274 (2019/05/15)
The first broad-scope catalytic asymmetric Tamura cycloaddition reactions are reported. Under the influence of anion-binding bifunctional catalysis a wide range of α,β-unsaturated N-trityl imines undergo reactions with enolisable anhydrides to form highly synthetically useful α-tetralone structures with excellent enantio- and -diastereocontrol. In stark contrast to the previous literature benchmarks, doubly activated or highly electron deficient alkenes are not required. A facile two-step, high yielding sequence can convert the cycloadducts to α-haloketones (challenging to generate catalytically by other means) with the net formation of two new C?C bonds and three new contiguous stereocentres with exquisite stereocontrol. A DFT study has provided insight into the catalyst mode of action and the origins of the observed enantiocontrol.
