Novel Benzylidene-9(10H)-anthracenones as Highly Active Antimicrotubule Agents. Synthesis, Antiproliferative Activity, and Inhibition of Tubulin Polymerization

Abstract

A novel series of 10-benzylidene-9(10H)-anthracenones and 10-(phenylmethyl)-9(10H)-anthracenones were synthesized and evaluated for antiproliferative activity in an assay based on K562 leukemia cells. The 3-hydroxy-4-methoxybenzylidene analogue 9h was found to be the most active compound (IC(50) K562: 20 nM). Structure-activity relationships are also considered. The highly active compound 9h and the 2,4-dimethoxy-3-hydroxybenzylidene analogue 9l were tested against five tumor cell lines using the XTT assay, including multidrug resistant phenotypes. Induction of cell death in a variety of tumor cell lines was determined in a monolayer assay using propidium iodide. Noteworthy, all compounds within the series induced elongations in K562 cells similar to vinblastine-treated cells. The effect of the lead compound 9h on K562 cell growth was associated with cell cycle arrest in G2/M. Concentrations for 50% KB/HeLa cells arrested in G2/M after treatment with 9h and 9l were determined and found to be in the range of 0.2 microM. Additionally, we monitored the dose dependent caspase-3-like protease activity in K562 cells and MCF-7/Casp-3 cells treated with 9h, indicating induction of apoptosis. Western blotting analysis demonstrated that 9h caused a shift in tubulin concentration from the polymerized state found in the cell pellet to the unpolymerized state found in the cell supernatant. Seven compounds strongly inhibited tubulin polymerization with activities higher or comparable to those of the reference compounds such as colchicine, podophyllotoxin, and nocodazole. In general, the antiproliferative activity correlated with inhibition of tubulin polymerization. The most active compounds strongly displaced [(3)H]colchicine from its binding site in the tubulin, yielding IC(50) values 3- to 4-fold lower than that of colchicine. The novel benzylidene-9(10H)-anthracenones described in the present study constitute an interesting group of highly active and easily accessible antimitotic agents that inhibit tubulin polymerization.

Characterization of a New Class of Androgen Receptor Antagonists with Potential Therapeutic Application in Advanced Prostate Cancer

“…S1). Chemicals belonging to the 10-benzylidene-10H-anthracen-9-one family have been previously implicated in some biological processes including inhibition of tubulin polymerization (21,38,39). However, this does not seem to be the mechanism of action observed in this work, as there was no correlation between antitubulin activity and either androgen displacement or androgen receptor transcriptional inhibition.…”

“…Some of these compounds have been previously reported (21) to act as inhibitors of tubulin polymerization and were obtained as described in that study. Compounds not mentioned therein were synthesized by an aldol-type condensation reaction of 10H-anthracen-9-one with appropriately substituted benzaldehydes under basic conditions in the presence of pyridine/piperidine (see details in Supplementary Materials and Methods).…”

“…As this chemical class has been reported to act as antimicrotubule agents with tubulin polymerization inhibitory activity (21), the tubulin polymerization activity was examined. Importantly, as reported previously, the tubulin polymerization inhibitory activity for the highly active androgen receptor inhibitors was not very pronounced, even for the most potent compound VPC-3033 (IC 50 ¼ 9.9 AE 0.39 mmol/L; Fig.…”

10-(4-Methylbenzylidene)anthracen-9(10H)-one

“…The title compound was synthesized as reported (Prinz et al, 2003) and crystallized EtOAc by slow evaporation technique.…”

“…For related structures, see: Wen & Li (2008); Zhou et al (2004). For the synthesis, see: Prinz et al (2003). For ring conformations, see: Cremer & Pople (1975).…”