Synthesis, antiproliferative activity and inhibition of tubulin polymerization by 1,5- and 1,8-disubstituted 10 H-anthracen-9-ones bearing a 10-benzylidene or 10-(2- oxo-2-phenylethylidene) moiety

• Published in: European journal of medicinal chemistry Vol. 45; no. 8; pp. 3420 - 3438
• Main Authors: Nickel, Holger C., Schmidt, Peter, Böhm, Konrad J., Baasner, Silke, Müller, Klaus, Gerlach, Matthias, Unger, Eberhard, Günther, Eckhard G., Prinz, Helge
• Format: Journal Article
• Language: English
• Published: Elsevier Masson SAS 2010
• Subjects: 10-(2-Oxo-2-phenylethylidene)-10 H-anthracen-9-ones; Antimitotic; Antiproliferative; Benzylidene-10 H-anthracen-9-ones; Colchicine; Tubulin; Antiproliferative; ITP; VCR; MTP; 10-(2-Oxo-2-phenylethylidene)-10 H-anthracen-9-ones; Benzylidene-10 H-anthracen-9-ones; ADR; Tubulin; Kip; TEBAC; DBU; ND; CSI; XTT; MDR; Colchicine; Antimitotic
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2010.04.032

A novel series of 1,5- and 1,8-disubstituted 10-benzylidene-10 H-anthracen-9-ones and 10-(2- oxo-2-phenylethylidene)-10 H-anthracen-9-ones was synthesized to assess the substituent effects on biological activity. The 3-hydroxy-2,4-dimethoxy-benzylidene analogue 16h displayed strong antiproliferative activity against several tumor cell lines, including multi-drug resistant phenotypes. Flow cytometric studies showed that KB/HeLa cells treated by elected compounds were arrested in the G2/M phases of the cell cycle. Among the compounds tested for inhibition of tubulin polymerization, 14 compounds proved to be exceptionally active with IC 50 values < 1 μM. In the 1,5-dichloro-derived series of benzylideneanthracenones, E/ Z isomers were separated and biological effects were monitored. We found that the olefinic geometry had no significant effect on biological activity. Furthermore, the E isomeric 1,5-dichloro-substituted phenacylidenes entirely proved to be more potent inhibitors of tubulin polymerization than the recently described 10-(2- oxo-2-phenylethylidene)-10 H-anthracen-9-ones. In conclusion, the present study improves understanding of the action of anthracenone-based tubulin polymerization inhibitors and contributes to the design of further potent anti-tubulin drugs. [Display omitted]