Synthesis And Insecticidal Activity Of Novel Camptothecin Derivatives Containing Analogs Of Chrysanthemic Acid Moieties

Creating high-efficient and environment-friendly pesticides is very important to produce the pollutionfree agriculture food and maintain the balance of the survival environmental of the human being. Theplant is the natural treasure-house of biological active compounds. It is aimed at finding insecticidalactive compounds from plant and using them as leading structure of new synthetic insecticides.According to reports, camptothecin (CPT) and its derivatives are now being explored as a class ofbotanical insecticide in agriculture due to its novel mode of action. In order to improve the insecticideactivity of camptothecin (CPT), ten novel camptothecin (1) and10-hydroxycamptothecin (2) derivatives(1a,1b,1c,1d,1e;2a,2b,2c,2d,2e) were designed and synthesized via esterification with thechrysanthemic acid moieties of pyrethroid insecticides, which have outstanding insecticide activity.The antifeeding activity of the target compounds was evaluated on the third-instar larvae ofSpodoptera exigua at the concentration of5mg/mL with the choice leaf disc methods. The resultsshowed that the antifeedant activities of title compounds apparently correlate with the newly introducedchrysanthemic acid moieties of the pyrethroid insecticides. Also, as the structures introduced to the leadcompounds becomed simpler, the antifeeding activity increased. This indicated that the antifeedingactivity of the compounds might be related to their steric hindrance. Furthermore, all of the compoundsderived from10-hydroxycamptothecin had better antifeeding activities than those derived from CPT.This showed that hydrophile reduction of10position could increase the bioactivity of compounds. Inthe meanwhile, the antifeeding activity might decrease if20position was substituted by moieties. It istherefore concluded that the10and20positions of a compound are necessary for the high antifeedingactivity against S. exigua.Contact toxicity of the title compounds against the third-instar larvae of S. exigua at the concentrationof10mg/mL was evaluated using a topical application method. The results showed that all of the targetcompounds derived from10-hydroxycamptothecin (except for2e) have better contact toxicities againstS. exigua. than their lead compound, especially2a （LC50was434.1mg/L）, which was found to be themost active insecticides of these two series of compounds. This proved that the introduction ofsubstituted groups to10position can increase the contact toxicity of camptothecin. As for the contacttoxicity of compounds derived from1, there was little change except for1e. Furthermore, the resultsshowed that although10-hydroxycamptothecin has weaker contact toxicity than CPT, all of the testedcompounds derived from10-hydroxycamptothecin exhibited better contact activities than those derivedfrom CPT. This could be related to the difference in binding with targets.The cytotoxicities of target compounds were measured on IOZCAS-Spex-II using a Cell Titer96Aqueous One Solution Cell Proliferation Assay kit. The results showed that compound2a was found tobe the most effective inhibitors among the10title compounds. The cytotoxicities of target compoundsincreased as the concentrations increased and the effect time prolonged. And all of the compoundsderived from10-hydroxycamptothecin had better cytotoxicities than those derived from CPT. These results were consistent with those of contact toxicity study.In order to explore the target of camptothecin and10-hydroxycamptothecin derivatives, wedetermined the inhibitory effect of these compounds on DNA relaxation by topoisomerase I (Top I)from IOZCAS-Spex-II cell extracts in vitro. The results showed that all of the tested compounds derivedfrom10-hydroxycamptothecin (except2b) inhibited the activity of Top I in vitro to a certain degreewhen the concentration was100μmol/L or less. However, the compounds1a-1e exhibited no inhibitoryactivity on DNA relaxation by Top I when the concentration was100μmol/L, which suggested that themechanism of compounds1a-1e is different from camptothecin, which exerts the toxic effect bytargeting Top I. As for compounds2a-2e, they exhibited a certain degree of inhibition on DNArelaxation of Top I but the inhibitory activity was lower than that of10-hydroxycamptothecin. Thus, wespeculated that there is another main targets for compounds2a-2e.