TFA-mediated Ring-opening Of Evodiamine To Prepare Tryptamine Derivatives And Their Anti-tumor Activity

Objective:Tryptamine and its derivatives have a variety of biological activities and are an important component in the human body.However,the structures of some tryptamine derivatives are complex and difficult to synthesize by conventional methods.Therefore,the search for a new source of tryptamine has an impetus for the study of tryptamine derivatives.The natural product evodiamine has a tryptamine skeleton and can be a source of tryptamine derivatives.Under certain conditions,the ring-opening of evodiamine can prepare new tryptamine derivatives.At the same time,evodiamine itself has anti-tumor effect.However,its hepatotoxicity and weak antitumor activity limit its application in anticancer.The ring-opened evodiamine becomes a tryptamine derivative with enhanced antitumor activity and reduced toxicity,which makes up for the defect of evodiamine.The ring-opening of evodiamine is a new method for obtaining tryptamine derivatives,which provides a new idea for the synthesis of tryptamine derivatives and has important value.Methods:1)Synthesis of N-13 substituted evodiamine derivatives:use DMF as solvent,under Na H alkaline conditions,use evodiamine as raw material,and carry out alkylation reaction with different alkylating reagents to obtain N-13 in medium yield Position-substituted evodiamine derivatives 2a-o.2)Synthesis of ring-opening derivatives of evodiamine:Series 1（3a-o）:The N-13 substituted evodiamine 2a-o obtained above,under reflux conditions,using chloroform as the solvent,under the catalysis of TFA,the ring opening of the C ring and the D ring occurs,resulting in medium to high yields of evodiamine derivatives 3a-o.Series 2（4a-o）:Using methanol as the solvent,intramolecular condensation of the evodiamine derivatives 3a-o under Na HCO₃conditions,closing the D ring,and obtaining evodiamine with an amino alcohol structure in medium to high yields derivatives 4a-o.3)In vitro activity test The CCK-8 method was used to detect the cell proliferation inhibition rate of 30 compounds（3a-o、4a-o）on human gastric cancer cell line（BGC803）,human colon cancer cell line（SW480）,and human normal liver cells（LO2）.Results:1)Using evicarine as a substrate,through alkylation,15 N-13 substituted evodiamine derivatives 2a-o were first generated.And the ring is opened under TFA conditions to generate 15 ring-opening derivatives 3a-o.Compound 3a-o generates ring-opening derivatives 4a-o of evodiamine with amino alcohol structure under alkaline conditions.The structure of the target compound was confirmed by¹H NMR,¹³C NMR,MS and other structural characterizations.2)The second and third step reaction conditions were screened and optimized.In the second step,the solvent is DCM,CHCl_3,etc.and the acidic condition is HCl,H₂SO₄,TFA,etc.The results showed that the ring-opening reaction of compound 2a-o was completed under the condition of TFA/CHCl₃,the product yield was high,and the by-products were few.In the third step,the solvent is CH₃OH,DCM,and the alkaline conditions are Na OH,Na HCO_3.The results showed that the use of Na HCO₃in methanol solution to react compound 3a-o to compound 4a-o,the reaction yield was the highest.3)Use the CCK-8 method to use evodiamine as a positive control.Tested the cell proliferation rate of 30 tryptamine derivatives（3a-o、4a-o）,including colon cancer cell line（SW480）,human gastric cancer cell line（BGC803）,human normal liver cell line（LO2）.The results showed that most of the tryptamine derivatives 3a-o had low toxicity to both types of cancer cells,but the tryptamine derivatives 4a-o showed moderate to strong cytotoxicity to both types of cancer cells.The difference is in the length of the fatty chain.The aliphatic side chain lengths of compounds 4d,4e,4j,4k,4l are all increased compared to CH₂,and the inhibition rate is 4j>4e>4k>4l>4d,indicating that the longer aliphatic N-13 side chain is generally It has a stronger cytotoxic effect on the above-mentioned cancer cell lines.The peak 4j is reached when the number of carbon atoms in the side chain reaches 6,and as the number of carbon atoms increases,the inhibition rate will decrease again.Overall,the in vitro antitumor activity of compound 4a-o was higher than that of compound 3a-o,and all these tryptamine derivatives showed reduced toxicity to LO2compared with evodiamine.Conclusion:The method designed in this paper uses the natural product evodiamine through alkylation,ring-opening under acidic conditions,and condensation under alkaline conditions.The target tryptamine derivatives can be successfully synthesized in a three-step reaction,with few side reactions,with moderate to high yields,and easy post-reaction treatment.,and in the in vitro anti-tumor activity test,compounds 4d,4e,4j,4k,and 4l all have certain inhibitory effects on SW480 and BGC803 cell lines,among which compound 4j has the best anti-tumor activity,and the inhibitory rate on SW480 and BGC803 more than 80%.And compared with evodiamine,the toxicity of these tryptamine derivatives to LO2 is much lower,so these tryptamine derivatives may be better lead compounds.The results show that the ring-opening of evodiamine is a new method for obtaining tryptamine derivatives,which provides a new idea for the synthesis of tryptamine derivatives,provides a way to obtain lead compounds,and has important value for new drug research..