458-11-7Relevant articles and documents
A comprehensive assessment of a new series of 5′,6′-difluorobenzotriazole-acrylonitrile derivatives as microtubule targeting agents (MTAs)
Riu, Federico,Sanna, Luca,Ibba, Roberta,Piras, Sandra,Bordoni, Valentina,Scorciapino, M. Andrea,Lai, Michele,Sestito, Simona,Bagella, Luigi,Carta, Antonio
, (2021/06/16)
Microtubules (MTs) are the principal target for drugs acting against mitosis. These compounds, called microtubule targeting agents (MTAs), cause a mitotic arrest during G2/M phase, subsequently inducing cell apoptosis. MTAs could be classified in two groups: microtubule stabilising agents (MSAs) and microtubule destabilising agents (MDAs). In this paper we present a new series of (E) (Z)-2-(5,6-difluoro-(1H)2H-benzo[d] [1,2,3]triazol-1(2)-yl)-3-(R)acrylonitrile (9a-j, 10e, 11a,b) and (E)-2-(1H-benzo[d] [1,2,3]triazol-1-yl)-3-(R)acrylonitrile derivatives (13d,j), which were recognised to act as MTAs agents. They were rationally designed, synthesised, characterised and subjected to different biological assessments. Computational docking was carried out in order to investigate the potential binding to the colchicine-binding site on tubulin. From this first prediction, the di-fluoro substitution seemed to be beneficial for the binding affinity with tubulin. The new fluorine derivatives, here presented, showed an improved antiproliferative activity when compared to the previously reported compounds. The biological evaluation included a preliminary antiproliferative screening on NCI60 cancer cells panel (1–10 μM). Compound 9a was selected as lead compound of the new series of derivatives. The in vitro XTT assay, flow cytometry analysis and immunostaining performed on HeLa cells treated with 9a showed a considerable antiproliferative effect, (IC50 = 3.2 μM), an increased number of cells in G2/M-phase, followed by an enhancement in cell division defects. Moreover, β-tubulin staining confirmed 9a as a MDA triggering tubulin disassembly, whereas colchicine-9a competition assay suggested that compound 9a compete with colchicine for the binding site on tubulin. Then, the co-administration of compound 9a and an extrusion pump inhibitor (EPI) was investigated: the association resulted beneficial for the antiproliferative activity and compound 9a showed to be client of extrusion pumps. Finally, structural superimposition of different colchicine binding site inhibitors (CBIs) in clinical trial and our MDA, provided an additional confirmation of the targeting to the predicted binding site. Physicochemical, pharmacokinetic and druglikeness predictions were also conducted and all the newly synthesised derivatives showed to be drug-like molecules.
Vinylene-bridged difluorobenzo[: C] [1,2,5]-thiadiazole (FBTzE): A new electron-deficient building block for high-performance semiconducting polymers in organic electronics
Asanuma, Yuya,Mori, Hiroki,Takahashi, Ryosuke,Nishihara, Yasushi
supporting information, p. 905 - 916 (2019/02/01)
A new class of an acceptor unit, vinylene-bridged 5,6-difluorobenzothiadiazole FBTzE, has been developed. Palladium-catalyzed Migita-Kosugi-Stille coupling reactions of 1 with 2, yielding 3 and its sequential dehydrogenative coupling with 4, readily affor
Activation of C-F bonds in ionic liquids catalyzed by nickel complex compounds
Prikhod'Kv,Adonin, N. Yu.,Parmon
, p. 33 - 38 (2013/11/19)
A nickel complex-catalyzed hydrodefluorination of acet(pentafluoroanilide) with zinc in ionic liquids resulted in the corresponding 2,3,4,5-tetrafluoro, 3,4,5-trifluoro, and 3,4-difluoro derivatives. The influence of the ionic liquid nature and the reaction conditions on its selectivity were studied, a possibility of the multiple reuse of the ionic liquids as the reaction media was demonstrated.
