Diverse Synthesis And Structure-activity Relationships Of Two Class Of Sesquiterpene Lactones As Anti-proliferative Agents

Natural products and their derivatives have been the main source of anticancer drugs.In recent years,active natural products have become an effective way to develop anti-tumor drugs.And several anti-cancer drug libraries have been established by semi-synthetic small molecules derived from natural products.Sesquiterpene lactone is a class of secondary metabolite with anticancer activity.In spite of their significant biological activities,sesquiterpene lactone derivatives and their bioactivity are lack of systematic.In this dissertation,we selected two class of sesquiterpene lactones as starting materials to synthesize 23 derivatives by introducing functional groups on the lead compounds.Among them,a)14 derivatives were modified by esterification,oxidization and free radical reaction from 1?-hydroxyalantolactone(1)and ivangustin(2);b)Another 9 derivatives were modified by radical reaction,nucleophilic substitution and click chemistry reaction from1,6-O,O-diacetylbritannilactone(3).These compounds were identified using spectroscopic methods,including 1H NMR,13 C NMR,HRMS and X-ray.To our best knowledge,the 23semi-synthetic compounds are all new.Firstly,the anti-proliferation structure-activity relationships(SAR)of sesquiterpene lactones derivatives were evaluated.For derivatives of compound 1 and 2,the anti-proliferation activity of oxidized derivatives increased,but the anti-proliferation activity of esterification derivatives decreased.For derivatives of compound 3,introduction of bromine in allylic position increased their antibacterial activities,in which derivative with two bromines(Br)in C9,14 position showed the highest anti-proliferation activity,a Br in C14 position has the higher,a Br in C9 position showed the lowest activity.Furthermore,introduction of triazole in C9 position increased the anti-proliferation activity.Among all these compounds,1h and 3c have higher activity of inhibiting cell proliferation than chemotherapy drugs etoposide(VP-16).Secondly,in order to explore the action mechanism of high active derivatives,the cell cycle analysis and apoptosis experiments were carried out.After treatment with 1h on cells,the proportion of cells in G0/G1 phase reduced,on the otherhand,the proportion of S and G2/M phase increased in a concentration-dependent relationship.Moreover,1h showed the apoptosis-induced activity by inducing procaspase 3 and PARP protein phosphorylation at low concentrations.In conclusion,we synthesized sesquiterpene lactone derivatives and analyzed the SAR.Two derivatives with high anti-proliferation activity were found and studied on the action mechanism.We proposed a new pathway for structure optimization of sesquiterpene lactone derivatives,meanwhile our research provided a theoretical basis for development anti-tumor drug candidates.