Approximately 50%o of Helicobacter pylori strains produce a toxin in vitro that induces vacuolation of eukaryotic cells. To determine whether ion transport pathways are important in the formation of toxin-induced vacuoles, HeLa cells were incubated with H. pylori toxin in the presence of nine different inhibitors of ion-transporting ATPases. Oligomycin, an inhibitor of predominantly FIF0-type ATPases, had no effect on toxin activity. Inhibitors of predominantly V-type ATPases, exemplified by bafilomycin Al, inhibited the formation of vacuoles in response to the H. pylori toxin and reversed the vacuolation induced by the toxin. In contrast, at concentrations of .100 nM, ouabain and digoxin, inhibitors of the Na+-K+ ATPase, potentiated the activity ofH. pylori toxin. The inhibitory effects of bafilomycin Al could not be overcome by the potentiating effects of ouabain. These data suggest that intact activity of the vacuolar ATPase of eukaryotic cells is a critical requirement in the pathogenesis of cell vacuolation induced by H. pyloni toxin and that vacuole formation by this toxin is associated with altered cation transport within eukaryotic cells.
Background:
Discovery of small molecules that inhibit tubulin polymerization is an attractive strategy for the
development of new and improved anti-proliferative agents.
Objective:
A series of novel 2-sulfonyl-1,1-diarylethenes were designed towards this end keeping in view of the favorable chemical
and pharmacological virtues of unsaturated sulfones.
Methods:
Rapid, convenient and efficient two-step assembly of the designed molecules was achieved by the vicinal iodosulfonylation-Suzuki coupling sequence.
Results:
As hypothesized, these compounds showed good anti-proliferative activity against different tissue-specific cancer cell lines:
MCF-7, DU-145, A-549, HepG2, and HeLa. The most active compound, p-nitrophenyl ring-bearing analog, exhibited an IC50 value of
0.90µM against A-549 cells. Flow cytometry studies on this derivative revealed that it arrests the cell cycle of A-549 cells at the G2/M
phase. This compound exhibited molecular binding to tubulin as well as tubulin polymerization inhibition comparable to that of
colchicine.
Conclusion:
A new class of potent, tubulin binding anticancer agents based on 1,1,-diarylvinyl sulfone scaffold has been designed
and synthesized.
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