Design,Synthesis And Biological Evaluation Of Novel 1,2,4-Triazole Derivatives As Tubulin Inhibitors

Microtubules are commonly found in eukaryotic cells in a protein skeleton,composed of α,and β-heterodimer subunits,and involved in the spindle and chromosome in the mitotic movement of cells,regulation of cell mitosis process,to maintain the normal morphology of cells.Modern science has shown that tumor cells,can be restricted without mitosis,and cell mitosis must rely on microtubules to form the spindle.Therefore,inhibition of tumor cells in the normal physiological function of tubulin is a very effective mechanism for the treatment of cancer.With the rapiddevelopment of medicinal chemistry and pharmacology,people have a more profound understanding of microtubules in the treatment of cancer,and tubulin inhibitors are becoming a hot research area for the treatment of cancer drugs.Initially,some natural products were reported as potent tubulin inhibitors,such as colchicine,CA-4,vinblastine,paclitaxel.With the rapid development of organic synthesis and computer-aided drug design technology,a large number of novel small molecule tubulin inhibitors,including triazole,pyridine,imidazole,pyrimidine,indole,sulfonamides were found.Among them,triazole scaffold has attracted great attention due to its potential biological activity,and the simple structure.Based on the our previously reported compound TR-33 and the well-knowntubulin inhibitor CA-4,three series of novel 1,2,4-triazole derivatives(Ⅰ,Ⅱ,Ⅲ series)which have not been reported in the literature,were designed and synthesized.The specific contents of the study are summarized as follows:1.In order to discover new anticancerdrug leads,22 compounds(Series I)was designed and synthesis,byreplacing of acetophenone group of our previously reported compound TR-33 withacetamidemoiety.In addition,24 novel N-amino 1,2,4-triazolederivatives Ⅱ without isoindole ringwere designed and synthesized based onour previouslyworks.2.A series of[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine compounds III were designed based on the structure of CA-4 and compound II with potential antitumor activityvia aring-closing strategy.3.Cytotoxic activities of all target compounds were tested by MTT method.Human colorectal cancer cell line(HT-29),human colon cancer cell line(HCT-116),human prostate cancer cell line(PC-3),human(MCF-7),human hepatocellular carcinoma cell line(HepG2),human lung cancer cell line(A549),human colon cancer cell line(HT-29),human gastric cancer cell line(MKN-45)were selected for antitumor activity in vitro.And the most active compounds were selected for flow cytometry.4.Some compounds with potant antiproliferative activities were selected for further evaluation for tubulin polymerization inhibition.And the results suggested thatmost of the compounds displayed a certain inhibiting effect on tubulin polymerization.5.In order to gain insights about the potential binding mode of N-amine 1,2,4-triazoles in tubulin,we performed docking simulations of the most activecompound Ⅱm and its relative binding free energy calculation.