Structural Modification Of Natural Product Tryptanthrin And Its Inhibitory Effect On Tumor Cell Proliferation

Natural products are one of the important sources of lead compounds in the research of new drugs,but they can not be directly developed into new drugs because of their limited sources,difficult extraction and purification,poor pharmacological activitities and some side effects.The natural product tryptanthrin belongs to the alkaloids of the indoloquinazolinones,tryptanthrins have anti-cancer,antibacterial and anti-inflammatory activities,but they can not be directly developed as a new drug because of their weak activities and low bioavailabilitis.Tryptanthrin is rarely studied in China,but widely studied abroad.In the past few years,we have studied the synthesis methods and some activities of tryptanthrin.We found a simple method to synthesis tryptanthrin and obtained some derivatives with better activities.In this paper,the synthesis method of tryptanthrin was further optimized,and the structure was modified and some active derivatives were obtained too.The optimal conditions for synthesis of tryptanthrin are as follows:isatin?and its derivatives?and isatoic anhydride?and its derivatives??1.0:1.05,mole ratio?were refluxed in CHCl₃for3.0 h with the aid of Et₃N in higher yield 93.1%.Twenty six tryptanthrins with substituent group in the D ring or A and D ring were successfully synthesized under the optimized conditions,of which fourteen compounds were new,which the yield of this method is40.7%?93.1%,and its high yield,low cost and simple post-treatment et al.The activities of 26 tryptanthrins were tested on HCT-116,A549,PC12 and MC-3T3-E1cell line by MTT.The results indicated that most of the tryptanthrins have fine inhibitory activities on tumor cells,among which 8-nitrotryptanthrin has the best inhibitory activity on human lung cancer cell line A549 and HCT-116,with IC₅₀value of 2.45?mol/L and3.52?mol/L;8-Fluorotryptanthrin has a strong inhibitory activity on PC12 cells,its IC₅₀value is 0.26?mol/L.In new compounds,3-chloro-9-bromotryptanthrin has good inhibitory activity on PC12 cells,and its IC₅₀value is 7.81?mol/L,2-chloro-8-trifluoromethoxytryptanthrin has good inhibitory activity on A549 cells and HCT-116 cells,with IC₅₀values is 19.11?mol/L and 21.53?mol/L respectively.Further analysis of the structure-activity relationship showed that the antitumor activity of D ring with mono-substituted derivatives was stronger than that of A and D ring double substituted derivatives,the activity of tryptanthrin with electron draw group is better than that of electron donor group,When tryptanthrin A and D rings has double groups,the A ring group reduces its activity.The activity of tryptanthrin derivatives with single group of-Cl at 7 or 9-position in D ring is almost higher than that of 2,7-2Cl,2,9-2Cl and 3,7-2Cl at A and D ring.In conclusion,through structural modification and activity analysis,we found that8-nitrotryptanthrin and 2-chloro-8-trifluoromethoxytryptanthrin have better inhibitory activity on lung cancer and colon cancer cells,as well as 8-fluorotryptanthrin and3-chloro-9-bromotryptanthrin have better inhibitory activity on adrenal pheochromocytoma cells.The results of this study lay a certain foundation for further research and the development of anti-cancer drugs.