Design,Synthesis And Antitumor Activity Evaluation Of Fluorinated Camptothecin Derivatives

Camptothecin is a small molecule compound with excellent antitumor activity derived from natural products.Camptothecin and its derivatives,as topo I specific inhibitors,are the focus of research and development of antitumor drugs.As camptothecin has poor water solubility and toxicity under physiological conditions,it can not be directly used in clinical.The derivatives of irinotecan,topotecan and belotecan obtained through structural modification have been successfully used in the treatment of colorectal cancer,ovarian cancer and prostate cancer,and there are more than ten drugs in the clinical research stage.Fluorine atom has been paid attention to because of its special properties.In the early stage of our research group,fluorine atom was successfully introduced at position 21 through E-ring defluoridation,and a kind of highly active camptothecin derivatives,represented by compound 11(see Chapter 1),was obtained.Its stability was enhanced and its toxicity was reduced.However,the problem of water solubility has not been solved.Carbamate fragments have been widely used in drug research and development.At present,there have been reports of camptothecin 10 carbamate derivatives,but no progress has been made in the study of camptothecin 20.In order to solve the problem of solubility of compound 11,11 carbamate derivatives were designed and synthesized at position 20.The in vitro antiproliferative activity of HCT116 and T24 and the inhibition activity of topo I of the synthesized compounds were tested.It was found that compound a7 was worthy of further study,and the stability study showed that a7 had high stability!Topotecan,a water-soluble camptothecin derivative,has been successfully developed by Mannich reaction to modify the structure of camptothecin.Therefore,we use Mannich reaction to enhance the water solubility of 21sfluoro-10-hydroxycamptothecin and introduce nitrogen-containing groups into A ring to synthesize seven compounds.At present,the antiproliferative activities of these compounds are in progress.At the same time,the research progress of camptothecin derivatives was reviewed.