Methoxy and bromo scans onN-(5-methoxyphenyl) methoxybenzenesulphonamides reveal potent cytotoxic compounds, especially against the human breast adenocarcinoma MCF7 cell line

Abstract

Thirty seven N-(5-methoxyphenyl)-4-methoxybenzenesulphonamide with methoxy or/and bromo substitutions (series 1-4) and with different substituents on the sulphonamide nitrogen have been synthesised. 21 showed sub-micromolar cytotoxicity against HeLa and HT-29 human tumour cell lines, and were particularly effective against MCF7. The most potent series has 2,5-dimethoxyanilines, especially the 4-brominated compounds 23-25. The active compounds inhibit microtubular protein polymerisation at micromolar concentrations, thus pointing at tubulin as the target. Co-treatment with the MDR inhibitor verapamil suggests that they are not MDR substrates. Compound 25 showed nanomolar antiproliferative potency. It severely disrupts the microtubule network in cells and arrests cells at the G 2 /M cell-cycle phase, thus confirming tubulin targeting. 25 triggered apoptotic cell death, and induced autophagy. Docking studies suggest binding in a distinct way to the colchicine site. These compounds are promising new antitumor agents acting on tubulin.

Potent and Selective Benzothiazole-Based Antimitotics with Improved Water Solubility: Design, Synthesis, and Evaluation as Novel Anticancer Agents

“…These results suggest that the glioblastoma cells have a special sensitivity to this class of microtubule drugs. Besides the high sensitivity of the glioblastoma cell lines, the breast cancer cell line MCF7 also shows a higher sensitivity to these compounds, which is in agreement with the previous results for the colchicine site tubulin inhibitors [57,58].…”

Novel Tetrazole Derivatives Targeting Tubulin Endowed with Antiproliferative Activity against Glioblastoma Cells

“…Concerning the effects on the different cell lines, each compound displayed similar IC 50 values for HeLa, HepG2, and HCT8 cells, whereas the HT-29 cells were less sensitive to the synthesized compounds, a feature that has been already observed for other colchicine site ligands and also the reference compounds CA-4, colchicine, and ABT-751 [57]. The most potent compounds, 10, 12, and 14, reached IC 50 values of 12-22 nM in U87 MG cells and 19-26 nM in the temozolomide-resistant T98G cells, showing similar potency to that of CA-4, higher potency than colchicine, and much higher potency than TMZ, whose IC 50 values are over 100 µm in both cell lines, thus suggesting that those compounds could be a good alternative to TMZ.…”

Panobinostat Synergistically Enhances the Cytotoxicity of Microtubule Destabilizing Drugs in Ovarian Cancer Cells

“…Microtubule-destabilizing agents, such as vincristine, combretastatin A4, ABT-751, or colchicine, have been employed for the treatment of different tumor types [ 31 , 38 , 39 ]. These compounds impair the microtubule network by disrupting their assembly, produce a G2/M cell cycle arrest, and induce apoptosis [ 14 , 38 , 39 , 40 , 41 , 42 ]. These effects are also produced by our previously described MDS [ 14 ] and by PILA9 .…”