Structure Activity Relationships And Anticancer Mechanisms Of Novel Colchicine Binding Site Tubulin Polymerization Inhibitors (CBSIs)

Colchicine binding site tubulin polymerization inhibitors(CBSIs)have many advantages over vinca binding inhibitors and taxoid binding inhibitors:(1)ability to overcome multidrug resistance,especially the multidrug resistance associated with the use of paclitaxel and docetaxel;(2)favorable pharmacokinetics and water solubility;(3)less side effects,because CBSIs have the good water solubility and thus exclude the need to use surfactants for solubilization which will cause the hypersensitivity reactions.In addition,some colchicine binding site tubulin polymerization inhibitors have entered clinical stages.However,there are no CBSIs approved by FDA to treat cancer.Therefore,it is meaningful to develop novel colchicine binding site tubulin polymerization inhibitors.In this work,seven series of compounds were synthesized as novel colchicine binding site tubulin polymerization inhibitors.There structure activity relationships and antitumor mechanisms were explored.1.Based on the antitumor effect of ?-lactam and the anti-microtubule effect of3,4,5-trimethoxyphenyl unit,seven series of anticancer compounds as novel colchicine binding site tubulin polymerization inhibitors were designed by molecular hybridization strategy.Chemical structures of these colchicine binding site inhibitors are ?-lactams?aromatic heterocyclic thioethers?benzothiazoles?1,2,3-triazoles?dihydroindole?chalcone-aminodithiocarbamates and thiophenes.136 target compounds were synthesized by wolff rearrangement ? [2+2]cycloaddition?oxidation?click reactions and so on.2.All these compounds were evaluated for their antiproliferative activity against gastric cancer MGC-803?prostate cancer PC-3?breast cancer MCF-7?esophageal cancer KYSE30?lung cancer A549?cervical cancer Hela?colon cancer HT29 and other cancer cells.The effects of substituents?substituent positions?aromatic heterocyclic fragments ? 3,4,5-trimethoxylphenyl and trifluoromethanesulfonyl units for the antiproliferative activity were investigated.Based on the three-dimensional structure of microtubule protein(PDB code: 1SA0),targeted compounds were docked to analyze their hydrogen bonds,hydrophobic and hydrophilic effects.3.Anticancer mechanisms of synthetic colchicine site inhibitors in vitro and in vivo were explored.The colchicine site inhibitors could inhibit cell growth and colony formation,induce apoptosis and DNA damage,reduce mitochondrial membrane potential,arrest cell cycke at G2/M phase,and affect epithelial mesenchymal transformation process.By immunofluorescence and EBI experiments,targeted compounds directly bond to colchicine site and inhibited microtubulin polymerization in a concentration-dependent manner.In addition,colchicine site inhibitors I-28 and VII-17 effectively inhibited MGC-803 xenograft tumor growth in nude mice without causing significant toxicity changes.