Author: Khandaker, Tashrique A.; Hess, Jessica D.; Aguilera, Renato; Andrei, Graciela; Snoeck, Robert; Schols, Dominique; Pradhan, Padmanava; Lakshman, Mahesh K.
Title: Synthesis and Evaluations of “1,4â€Triazolyl Combretacoumarins†and Desmethoxy Analogs Cord-id: 90pat7ij Document date: 2019_8_7
ID: 90pat7ij
Snippet: 1,4â€Triazolyl combretacoumarins have been prepared by linking the trimethoxyarene unit of combretastatin A4 with coumarins, via a 1,2,3â€triazole. For this, 4â€azidocoumarins were accessed by a sequential twoâ€step, oneâ€pot reaction of 4â€hydroxycoumarins with (benzotriazolâ€1â€yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), followed by reaction with NaN(3). In the reaction with BOP, a coumarinâ€derived phosphonium ion intermediate seems to form, leading to an O (4)â€
Document: 1,4â€Triazolyl combretacoumarins have been prepared by linking the trimethoxyarene unit of combretastatin A4 with coumarins, via a 1,2,3â€triazole. For this, 4â€azidocoumarins were accessed by a sequential twoâ€step, oneâ€pot reaction of 4â€hydroxycoumarins with (benzotriazolâ€1â€yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), followed by reaction with NaN(3). In the reaction with BOP, a coumarinâ€derived phosphonium ion intermediate seems to form, leading to an O (4)â€(benzotriazolyl)coumarin derivative. For the CuAAC reaction of azidocoumarins with 5â€ethynylâ€1,2,3â€trimethoxybenzene, catalytic [(MeCN)(4)Cu]PF(6) in CH(2)Cl(2)/MeOH with 2,6â€lutidine, at 50 (o)C, was suitable. The 4â€azidocoumarins were less reactive as compared to PhN(3) and the NBO coefficients of the azido groups were compared by DFT analysis. Compound solubility was a problem in biological assays. On the basis of the biological and solubility data of one 1,4â€triazolyl combretacoumarin, four analogs lacking one or two methoxy groups were synthesized. Reactivity differences among the phenylacetylenes were noted and the NBO coefficients of the alkynes were compared by DFT analysis. In cytotoxicity assays, 1â€phenylâ€4â€(3,4,5â€trimethoxyphenyl)â€1Hâ€1,2,3â€triazole showed activity in CEM and MDAâ€MBâ€231 cell lines by apoptosis. The desmethoxy 6â€bromoâ€4â€(4â€(4â€methoxyphenyl)â€1Hâ€1,2,3â€triazolâ€1â€yl)â€2Hâ€chromenâ€2â€one also showed cytotoxicity against the two cell lines, but this did not appear to be consistent with apoptosis. The antiviral activity of the compounds was unremarkable.
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