We report the synthesis and metabolic and biological evaluation of a series of 17 novel heterocyclic derivatives of isocombretastatin-A4 (iso-CA-4) and their structure−activity relationships. Among these derivatives, the most active compound, 4f, inhibited the growth of a panel of seven cancer cell lines with an IC 50 in the low nanomolar range. In addition, 4f showed interesting activity against CA-4-resistant colon-carcinoma cells and multidrug-resistant leukemia cells. It also induced G 2 /M cell-cycle arrest. Structural data indicated binding of 4f to the colchicine site of tubulin, likely preventing the curved-tostraight tubulin structural changes that occur during microtubule assembly. Also, 4f disrupted the blood-vessel-like assembly formed by human umbilical-vein endothelial cells in vitro, suggesting its function as a vascular-disrupting agent. An in vitro metabolism study of 4f showed its high human-microsomal stability in comparison with that of iso-CA-4. The physicochemical properties of 4f may be conducive to CNS permeability, suggesting that this compound may be a possible candidate for the treatment of glioblastoma.
In photodynamic therapy, the specificity of a photosensitizer and its penetration into tumor cells are crucial. We have analyzed the ability of newly synthesized meso-(tetraphenyl)porphyrins to be recognized by a model of mannose-specific proteins overexpressed at the surface of retinoblastoma cells. The specific interaction of porphyrin with Con A was studied by surface pressure measurements, fluorescence spectroscopy, dynamic light scattering, and QCM-D. The extent of porphyrins binding to Con A was highly dependent upon their chemical structure. Glycodendrimeric porphyrins showed the higher binding constant to Con A. The length of the spacer separating the sugar from the tetrapyrrolic ring appeared to be crucial in controlling the interaction of the compounds with the lectin in solution or immobilized onto a solid substrate. The methodology used proved to be efficient for the selection of potentially active compounds. The glycodendrimeric porphyrins, especially the derivative having the longer spacer, interacted more significantly with the lectin than the compound devoid of any sugar.
Designing multitarget drugs have raised considerable interest due to their advantages in the treatment of complex diseases such as cancer. Their design constitutes a challenge in antitumor drug discovery. The present study reports a dual inhibition of tubulin polymerization and HDAC activity. On the basis of 1,1-diarylethylenes ( isoCA-4) and belinostat, a series of hybrid molecules was successfully designed and synthesized. In particular compounds, 5f and 5h were proven to be potent inhibitors of both tubulin polymerization and HDAC8 leading to excellent antiproliferative activity.
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