Design,Synthesis And Structure-Activity Relationship Studies Of Camptothecin As Anticancer Drugs

Camptothecin(CPT),a unique pentacyclic quinoline alkaloid,was isolated from the Chinese tree Camptotheca acuminata by Monroe E.Wall and Mansukh C.Wani in 1958.It showed excellent antitumor activity,and was mainly used for colon cancer,ovarian cancer,liver cancer,bone cancer and leukemia treatment.Because of the unique anti-tumor mechanism against Topo I,there are a large number of camptothecin derivatives have been synthesized.As the result of research efforts,three CPT analogs,topotecan,irinotecan and belotecan were received governmental approval for the clinical treatment and fourteen additional analogs were currently under clinical evaluation.However,clinical use of camptothecin in cancer therapy was limited by its poor water solubility and unstable ability in human plasma.In order to synthesize a series of CPT analogs having improved biological activity and improved water solubility,A ring and 20(S)-of camptothecin were modified on the basis of the preliminary work.My thesis involves the following four research contents:Part I: The recent advances in camptothecin research,mode of action,structure-activity relationship,synthesis of camptothecin compounds and biological activity were reviewed and disscussed.Part II: Design,synthesis and structure-activity relationship studies of camptothecin A ring derivatives.As the main modification sites of the A ring of CPT,several 9,10-positions modified derivatives have been used clinically or have entered the preclinical study.Therefore,in this part,a series of hexacyclic camptothecins and 9,10-positions mono-or di-substituted camptothecins were synthesized economically and efficiently.The feasibility of the modified at 9,10-positions of camptothecin was further verified by the activity assay.Part III: Design,synthesis and antitumor activity studies of novel 9-piperazine camptothecin derivatives based on Mannich Reaction.Piperazine is a notable nitrogen-containing six-membered heterocyclic ring that plays an important role in the field of pharmaceutical chemistry.Many drugs contained piperazine or sulfonylpiperazine fragment with broad spectrum pharmacological activities that have been used in clinical.The idea of introducing a piperazine fragment to the 9-position of camptothecin using the Mannich reaction is similar to the synthetic method of topotecan.We also found that the sulfonylpiperazine fragment introduced to the 7-position of camptothecin was useful to improve antitumor activity of camptothecin.Therefore,a series of the C-9 methylpiperazine and methylsulfonylpiperazine camptothecin derivatives were designed in order to compare their biological activity and provide the basis for the follow-up work.Part IV: Design,synthesis and antitumor activity studies of cinnamic acid camptothecin derivatives.Cinnamic acid is well known as important anticancer agent and widely used in life sciences and medicinal chemistry,which has attracted intense attention from a large number of scientific researchers.In this paper,cinnamic acid was introduced into the camptothecin A-ring derivatives with good anti-tumor activity in order to synthesize a more promising camptothecin derivative with better antitumor activity and stable lactone ring.