1699-54-3Relevant articles and documents
Synthesis and SARs of dopamine derivatives as potential inhibitors of influenza virus PAN endonuclease
Liao, Yixian,Ye, Yilu,Li, Sumei,Zhuang, Yilian,Chen, Liye,Chen, Jianxin,Cui, Zining,Huo, Lijian,Liu, Shuwen,Song, Gaopeng
, (2020/01/21)
Currently, influenza PAN endonuclease has become an attractive target for development of new drugs to treat influenza infections. Herein we report the discovery of new PAN endonuclease inhibitors derived from a chelating agent dopamine moiety. A series of dopamine amide derivatives and their conformationally constrained 1,2,3,4-tetrahydroisoquinoline-6,7-diol-based analogs were elaborated and assayed against influenza virus A/WSN/33 (H1N1). Most compounds exhibited moderate to excellent antiviral activities, generating a preliminary SARs. Among them, compounds 14 and 19 showed stronger anti-IAV activity compared with the reference Peramivir. Moreover, 14 and 19 demonstrated a concentration-dependent inhibition of PAN endonuclease based on both FRET assay and SPR assay. Docking studies were also performed to elucidate the binding mode of 14 and 19 with the PAN protein and to identify amino acids involved in their mechanism of action, which were well consistent with the biological data. This finding was beneficial to laying the foundation for the rational development of more effective PAN endonuclease inhibitors.
2,3,9- and 2,3,11-Trisubstituted tetrahydroprotoberberines as D2 dopaminergic ligands
Párraga, Javier,Cabedo, Nuria,Andujar, Sebastián,Piqueras, Laura,Moreno, Laura,Galán, Abraham,Angelina, Emilio,Enriz, Ricardo D.,Ivorra, María Dolores,Sanz, María Jesús,Cortes, Diego
, p. 150 - 166 (2013/10/01)
Dopamine-mediated neurotransmission plays an important role in relevant psychiatric and neurological disorders. Nowadays, there is an enormous interest in the development of new dopamine receptors (DR) acting drugs as potential new targets for the treatment of schizophrenia or Parkinson's disease. Previous studies have revealed that isoquinoline compounds such as tetrahydroisoquinolines (THIQs) and tetrahydroprotoberberines (THPBs) can behave as selective D2 dopaminergic alkaloids since they share structural similarities with dopamine. In the present study we have synthesized eleven 2,3,9- and 2,3,11-trisubstituted THPB compounds (six of them are described for the first time) and evaluated their potential dopaminergic activity. Binding studies on rat striatal membranes were used to evaluate their affinity and selectivity towards D1 and D2 DR and establish the structure-activity relationship (SAR) as dopaminergic agents. In general, all the tested THPBs with protected phenolic hydroxyls showed a lower affinity for D1 and D2 DR than their corresponding homologues with free hydroxyl groups. In previous studies in which dopaminergic affinity of 1-benzyl-THIQs (BTHIQs) was evaluated, the presence of a Cl into the A-ring resulted in increased affinity and selectivity towards D2 DR. This is in contrast with the current study since the existence of a chlorine atom into the A-ring of the THPBs caused increased affinity for D1 DR but dramatically reduced the selectivity for D2 DR. An OH group in position 9 of the THPB (9f) resulted in a higher affinity for DR than its homologue with an OH group in position 11 (9e) (250 fold for D2 DR). None of the compounds showed any cytotoxicity in freshly isolated human neutrophils. A molecular modelling study of three representative THPBs was carried out. The combination of MD simulations with DFT calculations provided a clear picture of the ligand binding interactions from a structural and energetic point of view. Therefore, it is likely that compound 9d (2,3,9-trihydroxy-THPB) behave as D2 DR agonist since serine residues cluster are crucial for agonist binding and receptor activation.
Michael reactions of ascorbic acid, 4th communication: Nitrostyrene as a Michael acceptor toward vitamin C
Schmidt,Eger
, p. 11 - 16 (2007/10/02)
The nitrostyrene derivatives 1a-m, prepared by the reaction of nitromethane with the appropriate substituted benzaldehyde, were reacted with ascorbic acid in a Michael type reaction to the new compounds 2a-h. The structural assignment of the resulting mixture of diastereomers could be performed by means of two dimensional homo- and heterocorrelated NMR spectroscopy and comparison to known Michael adducts of ascorbic acid. Catalytic hydrogenolysis of 2 a yielded the rearranged compound 7, formed by intramolecular aminolysis in analogy to the rearrangement of the Michael adduct of ascorbic acid and methylvinylketone 3 given in the literature. On testing, the C-nucleoside 7 did not reveal virostatic or cytostatic effects.
