Synthesis And Bioactivity Of Topoisomerase - â…  Inhibitor Camptothecin Derivatives

Camptothecin (CPT,1), isolated from the tree Camptotheca acuminate, is a pentacyclic alkaloid with potent antitumor activity. Nowadays, four CPT derivatives have been applied in clinic for treating ovarian cancer, small cell lung cancer, colon cancer and gastric cancer owing to their specific action mechanism as inhibitors of Topoisomerase I.In this dissertation, there are three research topics related to the structure of CPT: the synthesis of some CPT derivatives as PET tracers, the studies on the reactivity of 9-dimethylamino-group in topotecan and the synthesis of a novel kind of CPT-amino acid conjugates as anti-tumor agents.In the first section, four CPT derivatives were designed as PET tracers for tumor diagnosis. It is prerequisite that the structure of the PET tracers should possess some groups which can bear the labeled elements such as 18F and 11C easily and feasibly. Three of the four derivatives were obtained successfully, which afforded the synthetic method and HPLC references to radiosynthesis. Herein, we also carried out the radiosynthesis and preliminary PET imaging study of 11C-labeled 10-methoxycamptothecin in normal ICR mice.In the process of synthesizing topotecan PET reference substance,10-hydroxy-9-(methoxymethyl)camptothcin (11), an unexpected methanolysis product of topotecan, was obtained. We attributed the specific chemical behavior of the 9-dimethylamino group of topotecan to the internal hydrogen-bonding between 10-hydroxy and the nitrogen atom in position 9. As a result, the scope of the reaction was examined systemically and a presumption of the reaction mechanism via an ortho-quinonemethide intermediate was made. Furthermore,6 oxygen-substituted compounds were screened against Human oral squamous cell carcinoma cells (KB), Human live cancer cells (HepG2), Mice colon carcinoma cells (C26) with 10-hydroxycamptothecin as reference compound and the bioactivity data suggested a possible structure activity relationship of the substituents in the position 9. Based on the fact that some basic biotic substances, especially amino acids, carbohydrates and bases, are largely ingested by the growing tumor cells and enriched in this region, a novel kind of CPT derivatives conjugating with the structure of mentioned basic biotic compounds were designed in order to improve their cancer cell targetability, antitumor activity, water solubility as well as stability at physiological pH. In this research,6 CPT-amino acid conjugates have been synthesized and screened on a series of cell lines in vitro. The SAR will be discussed and concluded later as we obtain the bioactivity data.