Design,Synthesis And Anti-tumor Activities Evaluations Of Mono-carbonyl Analogs Of Curcumin Incorporating Pyrazol Moiety

Objective To obtain new compounds with stronger anticancer activities,a serials of mono-carbonyl analogues of curcumim incorporating pyrazol moiety,（1E,4E）-1-phenyl-5-（pyrazol-4-yl）penta-1,4-dien-3-one derivatives,were designed and synthesized using curcumin as a leading compound.Their anticancer activities in vitro were evaluated by MTT assay against human gastric cancer cells（SGC7901）,human hepatocellular carcinoma cells（HepG2）and human lung cancer cells（A549）.Methods1.Design and synthesis of target compoundsThe 15 curcumin analogues I₁-I₁₅5 were designed and synthesized by replacing the unstable dicarbonyl structure in curcumin with monocarbonyl structure and replacing the benzene ring with pyrazole aromatic heterocycle.Phenylhydrazine was used as a starting material to condense with ethyl acetoacetate following by Vilsmeier reaction and substitution reaction,then the 1H-pyrazole-4-carbaldehyde derivatives were obtained.The benzaldehyde or substituted benzaldehyde reacted with acetone to generate the（E）-4-phenyl-3-buten-2-one derivatives.Finally,the target compounds were got by reaction of 1H-pyrazole-4-carbaldehyde derivatives with（E）-4-phenyl-3-buten-2-one derivatives.The structures of target compounds were characterized by IR,¹H-NMR and ¹³C-NMR techniques.2.Anticancer activities evaluations of the target compounds against 3 human cancer cell lines by MTT assayAnticancer activities of the 15 target compounds were evaluated by MTT assay against human gastric cancer cells（SGC7901）,human hepatocellular carcinoma cells（HepG2）and human lung cancer cells（A549）with curcumin,doxorubicin and hydroxycamptothecin as positive controls.The target compounds with the strongest anticancer activities were selected and the IC₅₀0 values were evaluated,which laid the foundation for further study.Results1.The 15 new（1E,4E）-1-phenyl-5-（pyrazol-4-yl）penta-1,4-dien-3-one derivatives were designed and synthesized,their structures were characterized by IR,¹H-NMR and¹³C-NMR techniques.2.Anticancer activities of 15 target compounds were evaluated by MTT assay against human gastric cancer cells（SGC7901）,human hepatocellular carcinoma cells（HepG2）and human lung cancer cells（A549）.The results showed that most of target compounds inhibited the 3 kinds of cancer cells when incubated with cancer cells at 24h,48h and72h.When target compounds incubated with cancer cells at 48h and 72h.the inhibition on cancer cells was the most obvious.The inhibition of compounds I₈ and I₉ on cancer cells was strongest in all of the test compounds.Their IC₅₀0 values were 1.77±0.24μM,3.20±0.04μM,3.31±0.05μM and 5.24±0.23μM,4.70±1.24μM,5.50±0.47μM,which were less than the positive controls of curcumin and doxorubicin.Conclusion1.The 15 mono-carbonyl analogues of curcumin incorporating pyrazol moiety were designed and synthesized.Their structures were characterized and the anticancer activities in vitro were evaluated by MTT assay using human gastric cancer cells（SGC7901）,human hepatocellular carcinoma cells（HepG2）and human lung cancer cells（A549）.The results showed that the inhibition of compound I₈ and I₉ on cancer cells was strongest,which were worthy of further study.2.Structure activity relationship studies showed that the anticacer activities of the target compounds were enhanced when the chlorine atom on the left side of the pyrazole ring was replaced by 2-methoxyphenoxy.When the right benzene ring was substituted with 3,4,5-trimethoxy or 3-methoxy-4 hydroxy groups,the anticacer activities of target compounds were also enhanced.