3--4--5--3-4-5-hexamethoxy-chalcone and metochalcone

Based on classical colchicine site ligands and a computational model of the colchicine binding site on beta tubulin, two classes of chalcone derivatives were designed, synthesized and evaluated for inhibition of tubulin assembly and toxicity in human cancer cell lines. Docking studies suggested that the chalcone scaffold could fit the colchicine site on tubulin in an orientation similar to that of the natural product. In particular, a 3,4,5-trimethoxyphenyl ring adjacent to the carbonyl group appeared to benefit the ligand-tubulin interaction, occupying the same subcavity as the corresponding moiety in colchicine. Consistent with modeling predictions, several 3,4,5-trimethoxychalcones showed improved cytotoxicity to murine acute lymphoblastic leukemia cells compared with a previously described parent compound, and inhibited tubulin assembly in vitro as potently as colchicine. The most potent chalcones inhibited the growth of human leukemia cell lines at nanomolar concentrations, caused microtubule destabilization and mitotic arrest in human cervical cancer cells, and inhibited human breast cancer cell migration in scratch wound and Boyden chamber assays.

Topics: Animals; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Cells, Cultured; Chalcones; Dose-Response Relationship, Drug; Humans; Jurkat Cells; Mice; Models, Chemical; Models, Molecular; Molecular Conformation; Molecular Structure; NIH 3T3 Cells; Polymerization; Tubulin

Efforts to identify potent small molecule inhibitors of Helicobacter pylori led to the evaluation of 23 3',4',5'-trimethoxychalcone analogues. Some of the compounds displayed potent antibacterial activity against H. pylori. Three most active and selective compounds 1, 7, and 13 also showed the bactericide activity against the reference as well as multidrug-resistant strains of H. pylori. Additionally, the aforementioned three compounds potentially inhibited the H. pylori adhesion and invasion to human gastric epithelial (AGS) cells. Furthermore, these selective compounds inhibited the H. pylori-induced gastric inflammation by reduced inflammatory mediator's nuclear factor kappa B activation, and the secretion of interleukin-8.

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents; Cell Line; Chalcones; Epithelial Cells; Gastritis; Helicobacter Infections; Helicobacter pylori; Host-Pathogen Interactions; Humans; Interleukin-8; NF-kappa B