Fluoro and pentafluorothio analogs of the antitumoral curcuminoid EF24 with superior antiangiogenic and vascular-disruptive effects
- Bioorg Med Chem. 2017 Sep 1;25(17):4894-4903. doi: 10.1016/j.bmc.2017.07.039.
- 1. Organic Chemistry Laboratory, University of Bayreuth, Universitaetsstrasse 30, 95447 Bayreuth, Germany.
- 2. Developmental Biology, University of Bayreuth, Universitaetsstrasse 30, 95447 Bayreuth, Germany.
- 3. University of Bucharest, Research Center for Integrated Analysis and Territorial Management, 4-12, Regina Elisabeta Avenue, Bucharest, 3rd district, 030018, Romania.
- 4. Organic Chemistry Laboratory, University of Bayreuth, Universitaetsstrasse 30, 95447 Bayreuth, Germany. Electronic address: [email protected].
A series of 14 analogs of the curcuminoid EF24, (3E,5E)-3,5-bis[(2-fluorophenyl)methylene]-4-piperidinone, bearing fluorine or pentafluorothio substituents, were prepared and tested for antiproliferative, vascular-disruptive, and antiangiogenic activity, as well as for their influence on Other cancer-relevant targets. They proved antiproliferative against eight Cancer cell lines with IC50 values in the low single-digit micromolar to triple-digit nanomolar range. Like EF24, the hexafluoro 3c and 3d and bis(pentafluorothio) 4f derivatives arrested HT-29 colon carcinoma cells in G2/M phase of the cell cycle, yet inhibited angiogenesis, e.g. in zebrafish larvae, to a much greater extent. The antimigratory effects in 518A2 melanoma cells of 3c, its regioisomer 3d, and of 4f, originate from an inhibition of NF-κB translocation. Moreover, 3c and 3d showed potential as vascular-disruptive agents in chorioallantoic/vitelline membrane (CA/VM) assays.