Design,Synthesis And Anticancer Activities Of Novel Luotonin A Analogs

Luotonin A is one of natural topoisomerase I inhibitor,which has low antitumor activity.In this study,in order to find promising lead compounds,a series of novel Luotonin A analogs were designed and synthesized and their in vitro antitumor activities and topoisomerase I inhibitory activity were performed.The details are as follows:1.Design and Synthesis of Novel Luotonin A AnalogsBy introducing halogen and substituted amino group on the E ring,opening C ring and replacing A,B rings,16 novel Luotonin A analogs were designed,which have not been reported before.The synthesis of the target compounds were completed by a series of reactions such as quinazolinone skeleton formation,carboxylic acid reduction,Mitsunobu reaction and nucleophilic substitution.2.Study on the antiproliferative activities of novel Luotonin A analogs in vitroThe MTT method was used to examine the antiproliferative activities of the novel Luotonin A analogs on HepG2,A549,MCF-7 and Hela tumor cells in vitro.Some compounds such as 4a,4h and 26 b had good antiproliferative activities.The structure-activity relationship showed that the introduction of piperazine-type substituents on the E ring of Luotonin A could increase the activity significantly;if the C ring was broken,the activities will be remarkably reduced.The substitution of naphthalene for quinoline ring also has a certain improvement in activity.3.Studies on topoisomerase I inhibition in vitro and molecular dockingDNA relaxation assessment was used to determine the inhibitory activity of the novel Luotonin A analogs on topoisomerase I.The results showed that most of the analogs of Luotonin A could inhibit topoisomerase I at 40 μM.Among which,compounds 4a and 26 b had stronger inhibitory activities on topoisomerase I than camptothecin.Moreover,molecular docking showed that the action mode of compounds 4a and 26 b was similar to that of camptothecin.Their five-membered ring skeletons could form an π-π stacking with DNA bases,and piperazines could form salt bridge with ASP-533.