Design, Synthesis And Antitumor Activity Of Novel Flavonoid Derivatives

Cancer is one of the main leading causes of death and sickness.Anticancer drugs are very effective to treat the malignancy.Traditional drugs are most of cytotoxic drugs while novel anticancer drugs pay more attention to the multi-tache of the occur and growth of the tumor.Flavonoids are important kind of natural products with diversiform function and medical activity.But the activities of most of flavonoids are not outstanding.In order to exploit novel flavonoid derivatives with high activities,we immerge three different bioactive units,such as,thioether,dithiocarbamate and combretastatin into the flavonoid framework based on the bioisosterism and the connecting principle of actively biological groups.Several f libraries of flavonoid compounds with structure diversity are constructed rapidly and effectively by the application of microwave irradiation,multi-component reaction and highly selective reaction. Based on the results of antiproliferative activity and structure-activity relationship,we succeed to find several lead structures with outstanding activity.The action mechanisms of representative lead compounds are studied by several biological technologies.1.The research progress of flavonoids,dithiocarbamates,proteasome inhibitors and Combretastatins are summarized in the paper.2.Two hundred and seven novel flavonoids and twenty one flavonoid copper complex were designed and synthesized.Their structures were characterized by ^â… H NMR,MS spectroscopes, element quantitative analysis.X-Ray single crystal analysis is used to confirm the structure of eleven representative compounds.3.By the MTT assay,we screen the antiproliferative activity of nearly most of synthesized compounds and succeed to find several kinds of lead compounds with outstanding activity. Dithiocarbamate flavonoids,related copper complex and chromone Combretastatin derivatives are very potent to be used as lead structure for the discovery of novel anticancer drug.Thioether:The IC₅₀ of compounds 3-substituted chromonesâ…¡aa,â…¡ab andâ…¡aj with methyl oxadiazol,methyl thiadiazol and bischromone show are less than 1μM to several tested tumor cell lines;Dithiocarbamate:2-dithiocarbamate(DTC) chromone:The IC₅₀ of 2-substituted chromonesâ…¤db,â…¤dc and 3-substituted chromonesâ… ac,â…¦bc,â…¦ca,â…¦dc are under 1μM to several tested tumor cell lines.Especially,the IC₅₀ of compoundsâ…¦dc to LM7,MDA-MB-435s,Hep-2 and MCF-7 cells drop to 0.24-0.44μM;DTC-copper complex:The IC₅₀ of DTC-coumarin complexâ…©â…¢-Cu aa,â…©â…¢-Cu ab,â…©â…¢-Cu ac to all five tested tumor cell lines are under 0.35μM. Exhilaratingly,the IC_s0 of these complex to SW-480 and Hep-2 tumor cell lines reached the level of 0.05-0.07μM;The IC₅₀ of complexâ…¤-Cu ab,â…¤-Cu ac,â…¤-Cu bb,â…¤-Cu cc,â…¤-Cu cd,â…¤-Cu db,â…¤-Cu dc to all four tested tumor cell lines are between 0.11μM and 0.30μM.under 0.35μM. Exhilaratingly,the IC₅₀ of these complexes to SW-480 and Hep-2 tumor cell lines;Chromone Combretastatins derivatives:The IC₅₀ of compoundâ…©â…£a to all five tested tumor cell lines are under 0.112μM.4.We also studied the action mechanism of representive lead compounds.Thioether chromoneâ…¡ab,2-DTC chromoneâ…¤dc and 3-DTC chromoneâ…¦bc can effectively arrest the cell cycle of colon cancer cell or breast cancer cell.Chromone Combretastatins derivativeâ…©â…£a can arrest the cell cycle of larynx cancer cell SW480 and or breast cancer cell MDA-MB-435s based on the results of flow activated cell sorting analysis,morphological change(STM & TEM),Annexin V-FITC/PI,MMP,and DNA Ladder. Treatment of HCCLM7 tumor-bearing nude mice withâ…©â…£a(60 mg/kg/d i.p.,1-35 days) resulted in significant inhibition(44.7%) of the tumor growth.DTC copper complexâ…©â…¢-Cu bb andâ…©â…¤-Cu dc show excellent inhibiting activity of prostate cancer cellular 26S proteasome and purified 20S proteasome.We can concluded that the primary target for DTC-copper complex with coumarin and chromone are the proteasome,and that inhibition of the proteasomal activity by DTC-copper complex is associated with apoptotic cancer cell death based on the results of dose-dependent and time-dependent experiments.5.The summary of structure-activity relationship of thioether,dithiocarbamte and Combretastatins give important direction for further optimization.