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).
Isoquinolinedione-urea hybrids: Synthesis, antibacterial evaluation, drug-likeness, molecular docking and DFT studies
?zkul, Ceren,Dengiz, Cagatay,Do?an, ?engül Dilem,Gündüz, Miyase G?zde,Han, M. ?hsan,K?prü, Semiha
, (2021/12/20)
In the present study, we applied the molecular hybridization approach to combine isoquinolinedione and urea pharmacophores in the same molecules. The hybrid compounds (IU1-IU14) were obtained by the reaction of 2-aminohomophthalimide and an equivalent amount of various isocyanate derivatives. After confirming the chemical structures and evaluating drug-likeness properties, the synthesized compounds were examined for their antibacterial activities against a wide range of bacteria. The compounds possessing lipophilic halogen substituents showed better activities against Gram-positive bacteria, particularly on Staphylococcus aureus strains. This activity trend was further supported by molecular docking studies in the ATP pocket of S. aureus DNA gyrase. Several important parameters such as, ionization potential (IP), electron affinity (EA), global chemical hardness (η), global softness (σ), and electronegativity (χ) were carried out to gain insights into the structural properties and stabilities of selected active compounds by means of density functional theory (DFT) at the B3LYP functional using basis set B3LYP/6–311G(d,p). Electrostatic potential maps (ESPs) and frontier orbital visualizations were further used to comment on molecular polarity and stability.
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.
Facile access to Fe(III)-complexing cyclic hydroxamic acids in a three-component format
Chupakhin, Evgeny,Bakulina, Olga,Dar’in, Dmitry,Krasavin, Mikhail
, (2019/03/19)
Cyclic hydroxamic acids can be viewed as effective binders of soluble iron and can therefore be useful moieties for employing in compounds to treat iron overload disease. Alternatively, they are analogs of bacterial siderophores (iron-scavenging metabolites) and can find utility in designing antibiotic constructs for targeted delivery. An earlier described three-component variant of the Castagnoli—Cushman reaction of homophthalic acid (via in situ cyclodehydration to the respective anhydride) was extended to involve hydroxylamine in lieu of the amine component of the reaction. Using hydroxylamine acetate and O-benzylhydroxylamine was key to the success of this transformation due to greater solubility of the reagents in refluxing toluene (compared to hydrochloride salt). The developed protocol was found suitable for multigram-scale syntheses of N-hydroxy- and N-(benzyloxy)tetrahydroisoquinolonic acids. The cyclic hydroxamic acids synthesized in the newly developed format have been tested and shown to be efficient ligands for Fe3+, which makes them suitable candidates for the above-mentioned applications.
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.
The base-catalysed Tamura cycloaddition reaction: Calculation, mechanism, isolation of intermediates and asymmetric catalysis
Lockett-Walters, Bruce,Trujillo, Cristina,Twamley, Brendan,Connon, Stephen
supporting information, p. 11283 - 11286 (2019/09/30)
A combined experimental and computational investigation has revealed that the base-catalysed Tamura cycloaddition between homophthalic anhydride and activated alkenes/alkynes-a reaction previously thought of as a Diels-Alder type process-proceeds via a stepwise mechanism involving conjugate addition and ring closure; which allowed the first catalytic asymmetric α-substitution reactions to be demonstrated with up to >99% ee.
Catalytic Asymmetric Cycloadditions between Aldehydes and Enolizable Anhydrides: Cis-Selective Dihydroisocoumarin Formation
Aiello, Maria Luisa,Farid, Umar,Trujillo, Cristina,Twamley, Brendan,Connon, Stephen J.
, p. 15499 - 15511 (2019/01/04)
In the presence of a trityl-substituted cinchona alkaloid-based catalyst, homophthalic, aryl succinic, and glutaconic anhydride derivatives reacted with aromatic and aliphatic aldehydes to produce cis-lactones in up to 90:10 dr and 99% ee. A DFT study has shown how the catalyst is uniquely able to bring about the opposite sense of diastereocontrol to that usually observed.
Efficient cyclodehydration of dicarboxylic acids with oxalyl chloride
Kantin, Grigory,Chupakhin, Evgeny,Dar'in, Dmitry,Krasavin, Mikhail
supporting information, p. 3160 - 3163 (2017/07/18)
Literature examples illustrating the use of oxalyl chloride to prepare dicarboxylic acid anhydrides are surprisingly limited. At the same time, we have discovered a method involving the use of this readily available reagent which allowed the preparation of novel cyclic anhydrides where other, more conventional, methods had failed. Herein, we demonstrate that the method is applicable to a wide diversity of substrates, delivers good to excellent yields of cyclic anhydrides without chromatographic purification and can be considered a synthetic tool of choice whenever dicarboxylic acid cyclodehydration is required.
Catalytic asymmetric Tamura cycloadditions involving nitroalkenes
Manoni, Francesco,Farid, Umar,Trujillo, Cristina,Connon, Stephen J.
, p. 1463 - 1474 (2017/02/15)
The first examples of asymmetric Tamura cycloaddition reactions involving singly activated alkenes are reported. Homophthalic anhydride reacts with α-methyl nitrosytrenes in the presence of an alkaloid-based catalyst to generate fused bicyclic aromatic ketone products with three new stereocentres (which are susceptible to subsequent equilibration) in 12-99% ee. An unusual equilibration process which occurs in methanolic medium in the absence of a recognisable base via proton transfer at the α-carbon of an ester was investigated experimentally and computationally.
Expeditious Synthesis of the Topoisomerase i Inhibitors Isoindolo[2,1- b ]isoquinolin-7(5 H)-one and the Alkaloid Rosettacin Based on Aryl Radical Cyclization of Enamide Generated by Using N -Acylaiminium Chemistry
El Blidi, Lahssen,Namoune, Aurélie,Bridoux, Alexandre,Nimbarte, Vijaykumar D.,Lawson, Ata Martin,Comesse, Sébastien,Da?ch, Adam
, p. 3583 - 3592 (2015/11/18)
A short and effective approach to the synthesis of the topoisomerase I inhibitor isoindolo[2,1-b]isoquinolin-7(5H)-one and the alkaloid rosettacin belonging to the aromathecin family is presented. The key step of this sequence, which resulted in the formation of a five-membered ring, was the aryl radical cyclization of enamides generated using N-acyliminium chemistry.
