10-(2-oxo-2-phenylethylidene)-10H-anthracen-9-ones as highly active antimicrotubule agents: synthesis, antiproliferative activity, and inhibition of tubulin polymerization.
A series of 10-(2-oxo-2-phenylethylidene)-10H-anthracen-9-ones were synthesized and evaluated for interactions with tubulin and for antiproliferative activity against a panel of human and rodent tumor cell lines. The 4-methoxy analogue 17b was most potent, displaying IC(50) values ranging from 40 to 80 nM, including multidrug resistant phenotypes, and had excellent activity as an inhibitor of tubulin polymerization (IC(50) = 0.52 microM). Concentration-dependent flow cytometric studies showed that KB/HeLa cells treated with 17b were arrested in the G2/M phases of the cell cycle (EC(50) = 90 nM). In competition experiments, 17b strongly displaced [(3)H]-colchicine from its binding site in the tubulin. The results obtained demonstrate that the antiproliferative activity is related to the inhibition of tubulin polymerization.
Prinz
Helge
H
Institute of Pharmaceutical and Medicinal Chemistry, Westphalian Wilhelms-University, Munster, Germany. prinzh@uni-muenster.de
Schmidt
Peter
P
Böhm
Konrad J
KJ
Baasner
Silke
S
Müller
Klaus
K
Unger
Eberhard
E
Gerlach
Matthias
M
Günther
Eckhard G
EG
D000873:Anthracenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003078:Colchicine / Q000378:metabolism; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D011485:Protein Binding; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C550360:10-(2-(4-methoxyphenyl)-2-oxoethylidene)-10H-anthracen-9-one; D000873:Anthracenes; D014404:Tubulin; D050257:Tubulin Modulators; D003078:Colchicine