Antitumor Activity Of Camptothecin Derivatives With Alkynyl Branched Chain At Position 7

Camptotheca acuminata,also known as dryland lotus,as a tall deciduous tree,can be used as medicine all over the body,mainly because it contains an anti-tumor alkaloid,scientific name camptothecin.With the continuous research progress,it was found that camptothecin showed a good inhibitory effect on most tumor cells.However,due to the structural characteristics of camptothecin,its physical and chemical properties are not ideal,and there are some problems such as cytotoxicity,low bioavailability and poor water solubility.After studying the structure-activity relationship,scholars at home and abroad have carried out a large number of chemical modifications,and a large number of derivatives with good biological activity can be obtained.However,a large number of derivatives have not been applied to clinical research,which shows that the structural modification of camptothecin is still in a hot period.In this paper,35 compounds(5 intermediates)with alcohol,thiocyano,trifluoromethylthio,selenium cyano,trifluoromethylselenyl and alkyl were synthesized from camptothecin substrate at position 7 by Sonogashira and nucleophilic substitution.The route of these six compounds was as short as 5 steps and as long as 7 steps,and the yield was in the range of 30%-66%.The fat solubility of the synthesized derivatives of camptothecin trifluoromethylthio and trifluoromethylselenyl was greatly improved,and the structures of the end products were confirmed by NMR and LC-MS.Finally,all derivatives were tested for the activity of human liver cancer cell Hep G2 and some derivatives were tested for the activity of mouse colon cancer cell CT26.The analysis of activity test results shows that camptothecin derivatives containing trifluoromethylthio group have better activity,some products of trifluoromethylselenyl group have better activity,and the activity of camptothecin derivatives substituted by cyclopropyl group has also been significantly improved.The research of this paper will provide data support and theoretical basis for the structural modification of camptothecin in the future.