Synthesis And Antitumor Activity Of Camptothecin Derivatives

Camptothecin(CPT) is a natural antitumor alkaloid isolated from Chinese tree Camptotheca acuminate.CPT and many of its derivatives are potent inhibitor of Topoisomerase I(Topo I).Their antitumor mechanism is that CPT and its derivatives could stabilize the Topo I-DNA complex and subsequently influence the republication of DNA and cause the cell death.During the last several decades, thousands of CPT derivatives were synthesized and their antitumor activities were evaluated.Three of the analogues Irinotecan,Topotecan and Belotecan have been approved as chemotherapeutic drugs used in clinic treatment on human cancers,and several other derivatives are now in different phases of clinic and pre-clinic trials. Base on the research on the structure-activity relationship(SAR) and reactive properties of CPT from literature,we have designed and synthesized 3 series of novel CPT analogues,and evaluated their antitumor activities to find promising new drugs.1.Synthesis and biological evaluation of 7-cycloalkylcamptothecin derivativesSubstitutions especially lipophilic groups at 7-position of CPT have instinct properties for activity in human blood.They could stop the interaction of carboxylate form of CPT E-ring with human serum albumin(HSA),and as a result,stabilize the E-ring lactone,enhance the biological activities and reduce the side effects. Substitutions are generally attached to 7-position via radical reactions.We applied the radical alkylation of alkylbromide to synthesize 7-alkylcamptothecin derivatives and developed a novel route for preparation 7-alkylcamptothecin derivatives.With this new method,we used much cheaper and more facile starting materials to get comparable or even higher yield than the methods reported in preparing 7-cycloalkylcamptothecin analogues.The result of antitumor activities demonstrated that the synthetic compounds of 7-cycloalkylcamptothecin derivatives have high activity which even up to 40 times higher than reference drug Topotecan.The SAR matched the conclusion we achieved before with QSAR study.The exceptional compound 7-cyclooctyl camptothecin showed low activity,which might imply a different model of combination with biological macromolecular due to its steric bulks. 2.Synthesis and biological evaluation of E-ring opened camptothecin derivativesAn intact lactone E-ring was once considered to be indispensable for CPT's activity.However,recent investigations indicated that CPT E-ring opened derivatives "hydroxyl-amide" and "ester-amid" compounds have comparable activity with CPT itself.We firstly introduced morpholine and imidazole groups to CPT "hydroxyl-amide" and "ester-amid" derivatives with simple procedures,and prepared 10 E-ring opened CPT analogues.Biological evaluation in vitro presented that activities of "hydroxyl-amide" compounds with morpholine group were high than that with imidazole group,and in "ester-amid" compounds,propionate derivatives have higher activities than acetate analogues.7/10 substitutions enhance the activitiy of the E-ring opened derivatives.The inhibition of "hydroxyl-amide" 3-5a on transplanted human tumors in mice and nude mice showed higher efficacy than reference drugs.The biological evaluation implied that CPT "hydroxyl-amide" compounds have their intrinsic antitumor property,not just play as the pre-drug of its ring-closed parent CPT.3.Synthesis and biological evaluation of E-ring five-membered lactone analogues of CPTThe high activities of homo-camptothecin and several E-ring modified CPT analogues change the opinions of the function of CPT E-ring.We designed and synthesized a series of E-ringγ-amide five-membered lactone analogues of CPT and evaluated their biological activity.The preparation of this series of compounds underwent a key procedure with three-step-tandem reaction.This domino reaction occurred on the PDC-CH₂Cl₂ condition after CPTs were opened by amines,and formed the target compounds.Derivatives bearing with terminal tertiary amines could not be achieved by the same strategy since tertiary amines were also oxidated by PDC.After different sequences were explored,the best strategy is connecting subsection to introduce tertiary amines.We gained more than 50γ-amide lactone analogues,including 7/10 substituted compounds,and 21 of them were tested to evaluate their activity.Disappointing,this E-ring modified CPT analogues presented low antitumor activity.Only one of them displayed comparable activity with reference drug Topotecan.Presumably,the 17-carbonyl in these compounds might compete with carbonyl in the D-ring in binding to biological macromolecular and caused the reduced activity.7/10 substitutions revealed two different contribution to the activity from SAR study,when butyl substituted at the N-amide,they favored the antitumor activity,but when the amide were substituted with tertiary amines,they disfavored the activities.In addition,amine radical reaction was employed for exploring the pathway to prepare 7-N substituted CPT analogues,though failed.The possible explanation was presented.