Design,Synthesis And Biological Activity Studies Of Novel Camptothecins Derivatives

Camptothecin(CPT)is an antitumor alkaloid isolated by Monroe E.Wall and Mansukh C.Wani in 1958 from Camptotheca acuminata,a tree native to China which has been extensively used in traditional Chinese medicine.Advances in the medicinal chemistry of CPT resulted in the semi-synthetic,more water-soluble analogues topotecan and irinotecan,which are used clinically for the treatment of colon and ovarian cancers,respectively.There are two major drawbacks to CPT and similar CPT agents that have made them less attractive for clinical use.First of all,CPT has unfavorable physical-chemical properties.CPT has very poor aqueous solubility,making it difficult to formulate.Second,it has severe clinical toxicities such as diarrhea,and hemorrhagic cystitis.Base on the research on the structure-activity relationship and the status of the present understanding of the mechanism of action of CPT,we have designed and synthesized two series of novel CPT analogues as well as two total synthesized CPT derivative to find promising new drugs.My thesis consists of the following contents:Part ?:We provide a detailed discussion of recent advances in the medicinal chemistry of camptothecin and introduced the camptothecin.Part ?:Design,snthesis and biological activity studies of novel acylthiourea camptothecins derivatives.The key role of naturally occurring amino acids in the chemistry of life and as structural units in peptides,proteins,and enzymes has led to intense study on the chemistry and biological activity of synthetic analogues,we designed and synthesis a series of ?-amino acid ester prodrugs of CPT as materials.Then we introduce an active functional group,acylthiourea,into this prodrug to stabilize the lactone ring and maximize therapeutic activity and minimize toxicity.Finially,we evaluated their cytotoxicity against four human tumor cell lines,human lung adenocarcinoma cells(A549),human breast cancer cells(MDA-MB-231),human oral epidermoid cancer cells(KB)and human oral epidermoid cancer cells drug-resistant strains of cells(KBvin).Part ?:Design,snthesis and biological activity studies of novel a-aminophosphonates camptothecins derivatives.Organophosphorus compounds are widely used as biologically active compounds,a-aminophosphonates,occupy an important place and reveal diverse and interesting biological and biochemical properties including antibacterial agents,antitumor agents and anti HIV agents.To solve the issue of lacking in structural diversity and poor aqueous solubility of CPT,based on the character of its structure,a series of a-aminophosphonates prodrugs of CPT's phosphonates were synthesized,meanwhile,cytotoxicity activity of the derivatives against four human tumor cell lines was evaluated.Part IV:Total synthesis study of camptothecin and its derivatiesSince the common drawback of industrial-scale extraction from the medical plants and the lacking of molecular diversity and complexity from natural source of camptothecin derivatives,we attempted in this work to develop a strategy to total synthesize camptothecin and its derivaties...