Rearch On Antitumor Effect Of Novel Synthesized Thiochromanone Derivatives In Vitro

Thiochromanones were reported to have extensive biological activities. Such usanti-inflammatory activity, antiemetim efficacy, anti-allergic, anti-platelet aggregativeactivity, antipsychotic effection. However, few reported have been focused on anti-tumoractivities. In our group, a variety of thiochromanone derivatives have been studied for asseyof the anti-tumor activities. It is found that they also have the effection of antitumor, and twonew thiochromanone derivatives have all ready been published. Developing newthiochromanones compounds with stronger antitumor activity is of great significance for thetreatment of tumor.In this work, anti-proliferative activities of28novel thiochromanone derivatives whichare synthesised in drug quality control key laboratory of hebei province and have not beenreported were investigated by MTT and effective antitumor compounds were selected.Andthen we stuidied the mechanism induce tumor apoptosis by preliminary.The result showed that16of the tested compounds have antitumor activity, while theremained12did not have. Among the16compounds,5of them showed the half maximalinhibitory concentration (IC50) values of4.1-70.59μmol·L1to11tumor cells and44.78-89.77μmol·L1to normal cells;3of them showed IC50of5.93-20.62μmol·L1tonormal cells42.93-44.86μmol·L1to normal cells, repectively. The remained3and5compounds showed IC50values of37.78-141.12μmol·L1and13.32-73.8μmol·L1,respectively; The inhibition effects of the16chemicals are superior to cisplatin at the sameconcentration (80.0μmol·L1). And the other7chemicals have no effects on the growth ofhuman tumor cell lines in vitro.(Z)-3-chloromethylene-5-methyl-thiochroman-4-ketone (CMTK) was chosen as theresearch object to investigate the mechanism of this compound, the results showed thatCMTK can dramatic inhibit cell proliferation, and anti-tumor activities at low concentrations(IC50:14.24±0.12μmol·L1). Importantly, the IC50of CMTK on MCF-7cells was muchhigher than that of cisplatin. Growth curves show that CMTK can inhibit cell proliferation intime-and dose-dependent manners. In cell-cycle analysis, proportions of MCF-7cells inG0/G1phase after12-h and24-h treatment with CMTK were significantly different from thecontrol group. In contrast, the proportion of cells in S phase tended to decrease, but notsignificantly. Use of TUNEL and flow cytometry indicated that CMTK induces apoptosis. InMCF-7cells, CMTK induces TNFR1production, activates caspase-8and caspase-9, and enhances caspase-3levels in a concentration-dependent way; however, CMTK does not affectproduction of DR3and TNF-α. These results suggest that the anti-tumor mechanism ofCMTK involves inducing apoptosis via caspase-8activation by death receptor, and caspase-9activation by the mitochondrial-dependent pathway. Our results provide preliminary data forfurther investigation of the apoptotic mechanism.