Study On The Total Synthesis Of Camptothecin Exatecan Derivatives

With the aging of the world’s population and the prevalence of unhealthy lifestyles,the incidence rate and mortality of cancer are increasing annually.To combat this serious situation,various therapeutic approaches have been explored,among which chemotherapy is still the most widely used effective method in cancer treatment.Camptothecin(CPT)is a bioactive alkaloid extracted from the Chinese Happy tree,which possesses a unique pentacyclic structure containing a pyrroloquinoline ring,a conjugated pyridine ring,and a hexatomic lactone ring.Due to its broad-spectrum antitumor activity in vitro and in vivo,and its significant inhibition of DNA topoisomerase I,CPT and its derivatives have been developed as small-molecule chemotherapy drugs in the pharmaceutical field.However,due to the poor stability,low solubility,and severe toxicity of CPT,it took many years of structural modification to develop various CPT drugs for clinical application and research.Exatecan derivatives have higher biological activity and better solubility than CPT,and their E-ring is more stable in human serum albumin.This article focuses on the design and synthesis of exatecan derivatives based on the concept of "active functional group introduction," and constructs structurally diverse CPT derivatives for drug activity screening.Much progress has been made in recent years in the structural modification of camptothecin by total synthetic methods,and several total synthetic strategies have been developed.In this paper,we designed the derivatives of exatecan focusing on the modification of the AB ring of camptothecin,and therefore chose the Friedlander synthesis method which does not affect the derivation of the AB ring.The synthesis of(S)-trione,a CDE ring intermediate of camptothecin required for the Friedlander synthesis method,was firstly explored.Using acetone and diethyl oxalate as starting materials,the 9-step reaction of Claisen condensation,nucleophilic substitution,Michael addition,heating decarboxylation,acetalization,ethylation,and catalytic reduction was used to prepare(S)-trione intermediate in 11% overall yield.Then,the exatecan derivative was synthesized in 8% overall yield by Friedlander synthesis using 2-fluoro-4-nitrotoluene as the starting material and undergoing 8-step reactions of benzene ring bromination,nitro reduction,acetylation,Heck coupling,olefin reduction,Friedel-Crafts acylation,hydrolysis,and Friedlander condensation.Meanwhile,after the construction of the camptothecin skeleton by Friedlander condensation,the camptothecin skeleton was chlorinated at position 7 by oxidation and nucleophilic substitution,and the 7-chloro-10-methyl-11-fluoro-20-acetoxycamptothecin was synthesized in 5% total yield by using 3-methyl-4-fluorobenzaldehyde as the starting material and undergoing 6 steps of benzene ring nitration,nitro reduction,Friedlander condensation,acetylation,oxidation and nucleophilic substitution.The 7-chloro-20-acetoxycamptothecin was semi-synthesized from camptothecin by the same method in a 3-step reaction in 29 % total yield.